Modulators of hsd17b13 expression

ABSTRACT

Methods, compounds, and compositions useful for inhibiting HSD expression are provided. Such compounds, compositions, and methods are useful for treating, preventing, or ameliorating a disease associated with HSD 17B 13.

SEQUENCE LISTING

The present application is being filed along with a Sequence Listing inelectronic format. The Sequence Listing is provided as a file entitledBIOL0350WOSEQ_ST25.txt created Dec. 13, 2019, which is 640 kb in size.The information in the electronic format of the sequence listing isincorporated herein by reference in its entirety.

FIELD

The present embodiments provide methods, compounds, and compositionsuseful for inhibiting hydroxysteroid 17-beta dehydrogenase 13(LOC345275; 17-beta hydroxysteroid dehydrogenase; HSD17B13; HSD17β13)expression, and in certain instances, reducing the amount of HSD17B13protein in a cell or animal, which can be useful for treating,preventing, or ameliorating a disease associated with HSD17B13.

BACKGROUND

Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of liverdisease from steatosis to nonalcoholic steatohepatitis (NASH) andcirrhosis. NAFLD is defined as fat accumulation in the liver exceeding5% by weight, in the absense of significant alcohol consumption,steatogenic medication, or hereditary disorders (Kotronen et al,Arterioscler Thromb. Vasc. Biol. 2008, 28: 27-38).

Non-alcoholic steatohepatitis (NASH) is NAFLD with signs of inflammationand hepatic injury. NASH is defined histologically by macrovesicularsteatosis, hepatocellular ballooning, and lobular inflammatoryinfiltrates (Sanyal, Hepatol. Res. 2011. 41: 670-4). NASH is estimatedto affect 2-3% of the general population. In the presence of otherpathologies, such as obesity or diabetes, the estimated prevalenceincreases to 7% and 62% respectively (Hashimoto et al, J. Gastroenterol.2011. 46(1): 63-69).

SUMMARY

Certain embodiments provided herein are compounds and methods forreducing the amount or activity of HSD17B13 mRNA, and in certainembodiments, reducing the amount or activity of HSD17B13 protein in acell or animal. In certain embodiments, the animal has a liver disease.In certain embodiments, the disease is NASH. In certain embodiments, thedisease is alcoholic steatohepatitis (ASH). In certain embodiments, thedisease is NAFLD. In certain embodiments, the disease is hepaticsteatosis. In certain embodiments, the disease is cirrhosis. In certainembodiments, the disease is hepatocellular carcinoma. In certainembodiments, the disease is alcoholic liver disease. In certainembodiments, the disease is HCV hepatitis. In certain embodiments, thedisease is chronic hepatitis. In certain embodiments, the disease ishereditary hemochromatosis. In certain embodiments, the disease isprimary sclerosing cholangitis. Certain compounds provided herein aredirected to compounds and compositions that reduce liver damage,steatosis, liver fibrosis, liver inflammation, liver scarring orcirrhosis, liver failure, liver enlargement, elevated transaminases, orhepatic fat accumulation in an animal.

Certain embodiments provided herein are directed to potent and tolerablecompounds and compositions useful for inhibiting HSD17B13 expression,which can be useful for treating, preventing, ameliorating, or slowingprogression of liver diseases. Certain embodiments provided herein aredirected to compounds and compositions that are more potent or havegreater therapeutic value than compounds publicly disclosed.

DETAILED DESCRIPTION

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory onlyand are not restrictive of the embodiments, as claimed. Herein, the useof the singular includes the plural unless specifically statedotherwise. As used herein, the use of “or” means “and/or” unless statedotherwise. Furthermore, the use of the term “including” as well as otherforms, such as “includes” and “included”, is not limiting.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.All documents, or portions of documents, cited in this application,including, but not limited to, patents, patent applications, articles,books, treatises, and GenBank and NCBI reference sequence records arehereby expressly incorporated by reference for the portions of thedocument discussed herein, as well as in their entirety.

It is understood that the sequence set forth in each SEQ ID NO in theexamples contained herein is independent of any modification to a sugarmoiety, an internucleoside linkage, or a nucleobase. As such, compoundsdefined by a SEQ ID NO may comprise, independently, one or moremodifications to a sugar moiety, an internucleoside linkage, or anucleobase. Compounds described by ION number indicate a combination ofnucleobase sequence, chemical modification, and motif.

Definitions

Unless otherwise indicated, the following terms have the followingmeanings:

“2′-deoxyfuranosyl sugar moiety” or “2′-deoxyfuranosyl sugar” means afuranosyl sugar moiety having two hydrogens at the 2′-position.2′-deoxyfuranosyl sugar moieties may be unmodified or modified and maybe substituted at positions other than the 2′-position or unsubstituted.A β-D-2′-deoxyribosyl sugar moiety in the context of an oligonucleotideis an unsubstituted, unmodified 2′-deoxyfuranosyl and is found innaturally occurring deoxyribonucleic acids (DNA).

“2′-deoxynucleoside” means a nucleoside comprising 2′-H(H) furanosylsugar moiety, as found in naturally occurring deoxyribonucleic acids(DNA). In certain embodiments, a 2′-deoxynucleoside may comprise amodified nucleobase or may comprise an RNA nucleobase (uracil).

“2′-O-methoxyethyl” (also 2′-MOE) refers to a 2′-O(CH₂)₂—OCH₃) in theplace of the 2′-OH group of a ribosyl ring. A 2′-O-methoxyethyl modifiedsugar is a modified sugar.

“2′-MOE nucleoside” (also 2′-O-methoxyethyl nucleoside) means anucleoside comprising a 2′-MOE modified sugar moiety.

“2′-substituted nucleoside” or “2-modified nucleoside” means anucleoside comprising a 2′-substituted or 2′-modified sugar moiety. Asused herein, “2′-substituted” or “2-modified” in reference to a sugarmoiety means a sugar moiety comprising at least one 2′-substituent groupother than H or OH.

“3′ target site” refers to the nucleotide of a target nucleic acid whichis complementary to the 3′-most nucleotide of a particular compound.

“5′ target site” refers to the nucleotide of a target nucleic acid whichis complementary to the 5′-most nucleotide of a particular compound.

“5-methylcytosine” means a cytosine with a methyl group attached to the5 position.

“About” means within ±10% of a value. For example, if it is stated, “thecompounds affected about 70% inhibition of HSD17B13”, it is implied thatHSD17B13 levels are inhibited within a range of 60% and 80%.

“Administration” or “administering” refers to routes of introducing acompound or composition provided herein to an individual to perform itsintended function. An example of a route of administration that can beused includes, but is not limited to parenteral administration, such assubcutaneous, intravenous, or intramuscular injection or infusion.

“Administered concomitantly” or “co-administration” means administrationof two or more compounds in any manner in which the pharmacologicaleffects of both are manifest in the patient. Concomitant administrationdoes not require that both compounds be administered in a singlepharmaceutical composition, in the same dosage form, by the same routeof administration, or at the same time. The effects of both compoundsneed not manifest themselves at the same time. The effects need only beoverlapping for a period of time and need not be coextensive.Concomitant administration or co-administration encompassesadministration in parallel or sequentially.

“Amelioration” refers to an improvement or lessening of at least oneindicator, sign, or symptom of an associated disease, disorder, orcondition. In certain embodiments, amelioration includes a delay orslowing in the progression or severity of one or more indicators of acondition or disease. The progression or severity of indicators may bedetermined by subjective or objective measures, which are known to thoseskilled in the art.

“Animal” refers to a human or non-human animal, including, but notlimited to, mice, rats, rabbits, dogs, cats, pigs, and non-humanprimates, including, but not limited to, monkeys and chimpanzees.

“Antisense activity” means any detectable and/or measurable activityattributable to the hybridization of an antisense compound to its targetnucleic acid. In certain embodiments, antisense activity is a decreasein the amount or expression of a target nucleic acid or protein encodedby such target nucleic acid compared to target nucleic acid levels ortarget protein levels in the absence of the antisense compound to thetarget.

“Antisense compound” means a compound comprising an oligonucleotide andoptionally one or more additional features, such as a conjugate group orterminal group. Examples of antisense compounds include single-strandedand double-stranded compounds, such as, oligonucleotides, ribozymes,siRNAs, shRNAs, ssRNAs, and occupancy-based compounds.

“Antisense inhibition” means reduction of target nucleic acid levels inthe presence of an antisense compound complementary to a target nucleicacid compared to target nucleic acid levels in the absence of theantisense compound.

“Antisense mechanisms” are all those mechanisms involving hybridizationof a compound with target nucleic acid, wherein the outcome or effect ofthe hybridization is either target degradation or target occupancy withconcomitant stalling of the cellular machinery involving, for example,transcription or splicing.

“Antisense oligonucleotide” means an oligonucleotide having a nucleobasesequence that is complementary to a target nucleic acid or region orsegment thereof. In certain embodiments, an antisense oligonucleotide isspecifically hybridizable to a target nucleic acid or region or segmentthereof.

“Bicyclic nucleoside” or “BNA” means a nucleoside comprising a bicyclicsugar moiety. “Bicyclic sugar” or “bicyclic sugar moiety” means amodified sugar moiety comprising two rings, wherein the second ring isformed via a bridge connecting two of the atoms in the first ringthereby forming a bicyclic structure. In certain embodiments, the firstring of the bicyclic sugar moiety is a furanosyl moiety. In certainembodiments, the bicyclic sugar moiety does not comprise a furanosylmoiety.

“Branching group” means a group of atoms having at least 3 positionsthat are capable of forming covalent linkages to at least 3 groups. Incertain embodiments, a branching group provides a plurality of reactivesites for connecting tethered ligands to an oligonucleotide via aconjugate linker and/or a cleavable moiety.

“Cell-targeting moiety” means a conjugate group or portion of aconjugate group that is capable of binding to a particular cell type orparticular cell types.

“cEt” or “constrained ethyl” means a ribosyl bicyclic sugar moietywherein the second ring of the bicyclic sugar is formed via a bridgeconnecting the 4′-carbon and the 2′-carbon, wherein the bridge has theformula: 4′-CH(CH₃)—O-2′, and wherein the methyl group of the bridge isin the S configuration.

“cEt nucleoside” means a nucleoside comprising a cEt modified sugarmoiety.

“Chemical modification” in a compound describes the substitutions orchanges through chemical reaction, of any of the units in the compoundrelative to the original state of such unit. “Modified nucleoside” meansa nucleoside having, independently, a modified sugar moiety and/ormodified nucleobase. “Modified oligonucleotide” means an oligonucleotidecomprising at least one modified internucleoside linkage, a modifiedsugar, and/or a modified nucleobase.

“Chemically distinct region” refers to a region of a compound that is insome way chemically different than another region of the same compound.For example, a region having 2′-O-methoxyethyl nucleotides is chemicallydistinct from a region having nucleotides without 2′-O-methoxyethylmodifications.

“Chimeric antisense compounds” means antisense compounds that have atleast 2 chemically distinct regions, each position having a plurality ofsubunits.

“Cleavable bond” means any chemical bond capable of being split. Incertain embodiments, a cleavable bond is selected from among: an amide,a polyamide, an ester, an ether, one or both esters of a phosphodiester,a phosphate ester, a carbamate, a di-sulfide, or a peptide.

“Cleavable moiety” means a bond or group of atoms that is cleaved underphysiological conditions, for example, inside a cell, an animal, or ahuman.

“Complementary” in reference to an oligonucleotide means the nucleobasesequence of such oligonucleotide or one or more regions thereof matchesthe nucleobase sequence of another oligonucleotide or nucleic acid orone or more regions thereof when the two nucleobase sequences arealigned in opposing directions. Nucleobase matches or complementarynucleobases, as described herein, are limited to the following pairs:adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C)and guanine (G), and 5-methyl cytosine (^(m)C) and guanine (G) unlessotherwise specified. Complementary oligonucleotides and/or nucleic acidsneed not have nucleobase complementarity at each nucleoside and mayinclude one or more nucleobase mismatches. By contrast, “fullycomplementary” or “100% complementary” in reference to oligonucleotidesmeans that such oligonucleotides have nucleobase matches at eachnucleoside without any nucleobase mismatches.

“Conjugate group” means a group of atoms that is attached to anoligonucleotide. Conjugate groups include a conjugate moiety and aconjugate linker that attaches the conjugate moiety to theoligonucleotide.

“Conjugate linker” means a group of atoms comprising at least one bondthat connects a conjugate moiety to an oligonucleotide.

“Conjugate moiety” means a group of atoms that is attached to anoligonucleotide via a conjugate linker.

“Contiguous” in the context of an oligonucleotide refers to nucleosides,nucleobases, sugar moieties, or internucleoside linkages that areimmediately adjacent to each other. For example, “contiguousnucleobases” means nucleobases that are immediately adjacent to eachother in a sequence.

“Designing” or “Designed to” refer to the process of designing acompound that specifically hybridizes with a selected nucleic acidmolecule.

“Diluent” means an ingredient in a composition that lackspharmacological activity, but is pharmaceutically necessary ordesirable. For example, the diluent in an injected composition can be aliquid, e.g. saline solution.

“Differently modified” means chemical modifications or chemicalsubstituents that are different from one another, including absence ofmodifications. Thus, for example, a MOE nucleoside and an unmodified DNAnucleoside are “differently modified,” even though the DNA nucleoside isunmodified. Likewise, DNA and RNA are “differently modified,” eventhough both are naturally-occurring unmodified nucleosides. Nucleosidesthat are the same but for comprising different nucleobases are notdifferently modified. For example, a nucleoside comprising a 2′-OMemodified sugar and an unmodified adenine nucleobase and a nucleosidecomprising a 2′-OMe modified sugar and an unmodified thymine nucleobaseare not differently modified.

“Dose” means a specified quantity of a compound or pharmaceutical agentprovided in a single administration, or in a specified time period. Incertain embodiments, a dose may be administered in two or more boluses,tablets, or injections. For example, in certain embodiments, wheresubcutaneous administration is desired, the desired dose may require avolume not easily accommodated by a single injection. In suchembodiments, two or more injections may be used to achieve the desireddose. In certain embodiments, a dose may be administered in two or moreinjections to minimize injection site reaction in an individual. Inother embodiments, the compound or pharmaceutical agent is administeredby infusion over an extended period of time or continuously. Doses maybe stated as the amount of pharmaceutical agent per hour, day, week ormonth.

“Dosing regimen” is a combination of doses designed to achieve one ormore desired effects.

“Double-stranded antisense compound” means an antisense compoundcomprising two oligomeric compounds that are complementary to each otherand form a duplex, and wherein one of the two said oligomeric compoundscomprises an oligonucleotide.

“Effective amount” means the amount of compound sufficient to effectuatea desired physiological outcome in an individual in need of thecompound. The effective amount may vary among individuals depending onthe health and physical condition of the individual to be treated, thetaxonomic group of the individuals to be treated, the formulation of thecomposition, assessment of the individual's medical condition, and otherrelevant factors.

“Efficacy” means the ability to produce a desired effect.

“Expression” includes all the functions by which a gene's codedinformation is converted into structures present and operating in acell. Such structures include, but are not limited to, the products oftranscription and translation.

“Gapmer” means an oligonucleotide comprising an internal region having aplurality of nucleosides that support RNase H cleavage positionedbetween external regions having one or more nucleosides, wherein thenucleosides comprising the internal region are chemically distinct fromthe nucleoside or nucleosides comprising the external regions. Theinternal region may be referred to as the “gap” and the external regionsmay be referred to as the “wings.”

“HSD17B13” means any nucleic acid or protein of HSD17B13. “HSD17B13nucleic acid” means any nucleic acid encoding HSD17B13. For example, incertain embodiments, a HSD17B13 nucleic acid includes a DNA sequenceencoding HSD17B13, an RNA sequence transcribed from DNA encodingHSD17B13 (including genomic DNA comprising introns and exons), and anmRNA sequence encoding HSD17B13. “HSD17B13 mRNA” means an mRNA encodinga HSD17B13 protein. The target may be referred to in either upper orlower case.

“HSD17B13 specific inhibitor” refers to any agent capable ofspecifically inhibiting HSD17B13 RNA and/or HSD17B13 protein expressionor activity at the molecular level. For example, HSD17B13 specificinhibitors include nucleic acids (including antisense compounds),peptides, antibodies, small molecules, and other agents capable ofinhibiting the expression of HSD17B13 RNA and/or HSD17B13 protein.

“Hybridization” means the annealing of oligonucleotides and/or nucleicacids. While not limited to a particular mechanism, the most commonmechanism of hybridization involves hydrogen bonding, which may beWatson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, betweencomplementary nucleobases. In certain embodiments, complementary nucleicacid molecules include, but are not limited to, an antisense compoundand a nucleic acid target. In certain embodiments, complementary nucleicacid molecules include, but are not limited to, an oligonucleotide and anucleic acid target.

“Immediately adjacent” means there are no intervening elements betweenthe immediately adjacent elements of the same kind (e.g. no interveningnucleobases between the immediately adjacent nucleobases).

“Individual” means a human or non-human animal selected for treatment ortherapy.

“Inhibiting the expression or activity” refers to a reduction orblockade of the expression or activity relative to the expression ofactivity in an untreated or control sample and does not necessarilyindicate a total elimination of expression or activity.

“Internucleoside linkage” means a group or bond that forms a covalentlinkage between adjacent nucleosides in an oligonucleotide. “Modifiedinternucleoside linkage” means any internucleoside linkage other than anaturally occurring, phosphate internucleoside linkage. Non-phosphatelinkages are referred to herein as modified internucleoside linkages.

“Lengthened oligonucleotides” are those that have one or more additionalnucleosides relative to an oligonucleotide disclosed herein, e.g. aparent oligonucleotide.

“Linked nucleosides” means adjacent nucleosides linked together by aninternucleoside linkage.

“Linker-nucleoside” means a nucleoside that links an oligonucleotide toa conjugate moiety. Linker-nucleosides are located within the conjugatelinker of a compound. Linker-nucleosides are not considered part of theoligonucleotide portion of a compound even if they are contiguous withthe oligonucleotide.

“Mismatch” or “non-complementary” means a nucleobase of a firstoligonucleotide that is not complementary to the correspondingnucleobase of a second oligonucleotide or target nucleic acid when thefirst and second oligonucleotides are aligned. For example, nucleobasesincluding but not limited to a universal nucleobase, inosine, andhypoxanthine, are capable of hybridizing with at least one nucleobasebut are still mismatched or non-complementary with respect to nucleobaseto which it hybridized. As another example, a nucleobase of a firstoligonucleotide that is not capable of hybridizing to the correspondingnucleobase of a second oligonucleotide or target nucleic acid when thefirst and second oligonucleotides are aligned is a mismatch ornon-complementary nucleobase.

“Modulating” refers to changing or adjusting a feature in a cell,tissue, organ or organism. For example, modulating HSD17B13 RNA can meanto increase or decrease the level of HSD17B13 RNA and/or HSD17B13protein in a cell, tissue, organ or organism. A “modulator” effects thechange in the cell, tissue, organ or organism. For example, a HSD17B13compound can be a modulator that decreases the amount of HSD17B13 RNAand/or HSD17B13 protein in a cell, tissue, organ or organism.

“MOE” means methoxyethyl.

“Monomer” refers to a single unit of an oligomer. Monomers include, butare not limited to, nucleosides and nucleotides.

“Motif” means the pattern of unmodified and/or modified sugar moieties,nucleobases, and/or internucleoside linkages, in an oligonucleotide.

“Natural” or “naturally occurring” means found in nature.

“Non-bicyclic modified sugar” or “non-bicyclic modified sugar moiety”means a modified sugar moiety that comprises a modification, such as asubstituent, that does not form a bridge between two atoms of the sugarto form a second ring.

“Nucleic acid” refers to molecules composed of monomeric nucleotides. Anucleic acid includes, but is not limited to, ribonucleic acids (RNA),deoxyribonucleic acids (DNA), single-stranded nucleic acids, anddouble-stranded nucleic acids.

“Nucleobase” means a heterocyclic moiety capable of pairing with a baseof another nucleic acid. As used herein a “naturally occurringnucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), andguanine (G). A “modified nucleobase” is a naturally occurring nucleobasethat is chemically modified. A “universal base” or “universalnucleobase” is a nucleobase other than a naturally occurring nucleobaseand modified nucleobase, and is capable of pairing with any nucleobase.

“Nucleobase sequence” means the order of contiguous nucleobases in anucleic acid or oligonucleotide independent of any sugar orinternucleoside linkage.

“Nucleoside” means a compound comprising a nucleobase and a sugarmoiety. The nucleobase and sugar moiety are each, independently,unmodified or modified. “Modified nucleoside” means a nucleosidecomprising a modified nucleobase and/or a modified sugar moiety.Modified nucleosides include abasic nucleosides, which lack anucleobase.

“Oligomeric compound” means a compound comprising a singleoligonucleotide and, optionally, one or more additional features, suchas a conjugate group or terminal group.

“Oligonucleotide” means a polymer of linked nucleosides each of whichcan be modified or unmodified, independent one from another. Unlessotherwise indicated, oligonucleotides consist of 8-80 linkednucleosides. “Modified oligonucleotide” means an oligonucleotide,wherein at least one sugar, nucleobase, or internucleoside linkage ismodified. “Unmodified oligonucleotide” means an oligonucleotide thatdoes not comprise any sugar, nucleobase, or internucleosidemodification.

“Parent oligonucleotide” means an oligonucleotide whose sequence is usedas the basis of design for more oligonucleotides of similar sequence butwith different lengths, motifs, and/or chemistries. The newly designedoligonucleotides may have the same or overlapping sequence as the parentoligonucleotide.

“Parenteral administration” means administration through injection orinfusion. Parenteral administration includes subcutaneousadministration, intravenous administration, intramuscularadministration, intraarterial administration, intraperitonealadministration, or intracranial administration, e.g. intrathecal orintracerebroventricular administration.

“Pharmaceutically acceptable carrier or diluent” means any substancesuitable for use in administering to an individual. For example, apharmaceutically acceptable carrier can be a sterile aqueous solution,such as PBS or water-for-injection.

“Pharmaceutically acceptable salts” means physiologically andpharmaceutically acceptable salts of compounds, such as oligomericcompounds or oligonucleotides, i.e., salts that retain the desiredbiological activity of the parent compound and do not impart undesiredtoxicological effects thereto.

“Pharmaceutical agent” means a compound that provides a therapeuticbenefit when administered to an individual.

“Pharmaceutical composition” means a mixture of substances suitable foradministering to an individual. For example, a pharmaceuticalcomposition may comprise one or more compounds or salt thereof and asterile aqueous solution.

“Phosphorothioate linkage” means a modified phosphate linkage in whichone of the non-bridging oxygen atoms is replaced with a sulfur atom. Aphosphorothioate internucleoside linkage is a modified internucleosidelinkage.

“Phosphorus moiety” means a group of atoms comprising a phosphorus atom.In certain embodiments, a phosphorus moiety comprises a mono-, di-, ortri-phosphate, or phosphorothioate.

“Portion” means a defined number of contiguous (i.e., linked)nucleobases of a nucleic acid. In certain embodiments, a portion is adefined number of contiguous nucleobases of a target nucleic acid. Incertain embodiments, a portion is a defined number of contiguousnucleobases of an oligomeric compound.

“Prevent” refers to delaying or forestalling the onset, development orprogression of a disease, disorder, or condition for a period of timefrom minutes to indefinitely.

“Prodrug” means a compound in a form outside the body which, whenadministered to an individual, is metabolized to another form within thebody or cells thereof. In certain embodiments, the metabolized form isthe active, or more active, form of the compound (e.g., drug). Typicallyconversion of a prodrug within the body is facilitated by the action ofan enzyme(s) (e.g., endogenous or viral enzyme) or chemical(s) presentin cells or tissues, and/or by physiologic conditions.

“Reduce” means to bring down to a smaller extent, size, amount, ornumber.

“RefSeq No.” is a unique combination of letters and numbers assigned toa sequence to indicate the sequence is for a particular targettranscript (e.g., target gene). Such sequence and information about thetarget gene (collectively, the gene record) can be found in a geneticsequence database. Genetic sequence databases include the NCBI ReferenceSequence database, GenBank, the European Nucleotide Archive, and the DNAData Bank of Japan (the latter three forming the InternationalNucleotide Sequence Database Collaboration or INSDC).

“Region” is defined as a portion of the target nucleic acid having atleast one identifiable structure, function, or characteristic.

“RNAi compound” means an antisense compound that acts, at least in part,through RISC or Ago2, but not through RNase H, to modulate a targetnucleic acid and/or protein encoded by a target nucleic acid. RNAicompounds include, but are not limited to double-stranded siRNA,single-stranded RNA (ssRNA), and microRNA, including microRNA mimics.

“Segments” are defined as smaller or sub-portions of regions within anucleic acid.

“Side effects” means physiological disease and/or conditionsattributable to a treatment other than the desired effects. In certainembodiments, side effects include injection site reactions, liverfunction test abnormalities, renal function abnormalities, livertoxicity, renal toxicity, central nervous system abnormalities,myopathies, and malaise. For example, increased aminotransferase levelsin serum may indicate liver toxicity or liver function abnormality. Forexample, increased bilirubin may indicate liver toxicity or liverfunction abnormality.

“Single-stranded” in reference to a compound means the compound has onlyone oligonucleotide.

“Self-complementary” means an oligonucleotide that at least partiallyhybridizes to itself. A compound consisting of one oligonucleotide,wherein the oligonucleotide of the compound is self-complementary, is asingle-stranded compound. A single-stranded compound may be capable ofbinding to a complementary compound to form a duplex.

“Sites” are defined as unique nucleobase positions within a targetnucleic acid.

“Specifically hybridizable” refers to an oligonucleotide having asufficient degree of complementarity between the oligonucleotide and atarget nucleic acid to induce a desired effect, while exhibiting minimalor no effects on non-target nucleic acids. In certain embodiments,specific hybridization occurs under physiological conditions.

“Specifically inhibit” with reference to a target nucleic acid means toreduce or block expression of the target nucleic acid while exhibitingfewer, minimal, or no effects on non-target nucleic acids. Reductiondoes not necessarily indicate a total elimination of the target nucleicacid's expression.

“Standard cell assay” means assay(s) described in the Examples andreasonable variations thereof

“Standard in vivo experiment” means the procedure(s) described in theExample(s) and reasonable variations thereof.

“Stereorandom chiral center” in the context of a population of moleculesof identical molecular formula means a chiral center having a randomstereochemical configuration. For example, in a population of moleculescomprising a stereorandom chiral center, the number of molecules havingthe (S) configuration of the stereorandom chiral center may be but isnot necessarily the same as the number of molecules having the (R)configuration of the stereorandom chiral center. The stereochemicalconfiguration of a chiral center is considered random when it is theresult of a synthetic method that is not designed to control thestereochemical configuration. In certain embodiments, a stereorandomchiral center is a stereorandom phosphorothioate internucleosidelinkage.

“Sugar moiety” means an unmodified sugar moiety or a modified sugarmoiety. As used herein, “unmodified sugar moiety” means a β-D-ribosylmoiety, as found in naturally occurring RNA, or a β-D-2′-deoxyribosylsugar moiety as found in naturally occurring DNA. As used herein,“modified sugar moiety” or “modified sugar” means a sugar surrogate or afuranosyl sugar moiety other than a β-D-ribosyl or aβ-D-2′-deoxyribosyl. Modified furanosyl sugar moieties may be modifiedor substituted at a certain position(s) of the sugar moiety,substituted, or unsubstituted, and they may or may not have astereoconfiguration other than β-D-ribosyl. Modified furanosyl sugarmoieties include bicyclic sugars and non-bicyclic sugars.

“Sugar surrogate” means a modified sugar moiety that does not comprise afuranosyl or tetrahydrofuranyl ring (is not a “furanosyl sugar moiety”)and that can link a nucleobase to another group, such as aninternucleoside linkage, conjugate group, or terminal group in anoligonucleotide. Modified nucleosides comprising sugar surrogates can beincorporated into one or more positions within an oligonucleotide andsuch oligonucleotides are capable of hybridizing to complementaryoligomeric compounds or nucleic acids.

“Synergy” or “synergize” refers to an effect of a combination that isgreater than additive of the effects of each component alone at the samedoses.

“Target gene” refers to a gene encoding a target.

“Targeting” means the specific hybridization of a compound to a targetnucleic acid in order to induce a desired effect.

“Target nucleic acid,” “target RNA,” “target RNA transcript” and“nucleic acid target” all mean a nucleic acid capable of being targetedby compounds described herein.

“Target region” means a portion of a target nucleic acid to which one ormore compounds is targeted.

“Target segment” means the sequence of nucleotides of a target nucleicacid to which a compound is targeted. “5′ target site” refers to the5′-most nucleotide of a target segment. “3′ target site” refers to the3′-most nucleotide of a target segment.

“Terminal group” means a chemical group or group of atoms that iscovalently linked to a terminus of an oligonucleotide.

“Therapeutically effective amount” means an amount of a compound,pharmaceutical agent, or composition that provides a therapeutic benefitto an individual.

“Treat” refers to administering a compound or pharmaceutical compositionto an animal in order to effect an alteration or improvement of adisease, disorder, or condition in the animal.

Certain Embodiments

Certain embodiments provide methods, compounds and compositions forinhibiting HSD17B13 expression.

Certain embodiments provide compounds targeted to a HSD17B13 nucleicacid. In certain embodiments, the HSD17B13 nucleic acid has the sequenceset forth in RefSeq or GENBANK Accession No. NM_178135.4 (incorporatedby reference, disclosed herein as SEQ ID NO: 1), the complement ofGENBANK Accession No. NC_000004.12 truncated from nucleotides 87301001to U.S. Pat. No. 87,326,000 (incorporated by reference, disclosed hereinas SEQ ID NO: 2), the sequence listed as SEQ ID NO: 3, or GENBANKAccession No. NM_001136230.2 (incorporated by reference, disclosedherein as SEQ ID NO: 4). In certain embodiments, the compound is anantisense compound or oligomeric compound. In certain embodiments, thecompound is single-stranded. In certain embodiments, the compound isdouble-stranded.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of 8-2896. In certain embodiments, thecompound is an antisense compound or oligomeric compound. In certainembodiments, the compound is single-stranded. In certain embodiments,the compound is double-stranded. In certain embodiments, the modifiedoligonucleotide consists of 10 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 9 to 80 linked nucleosides and having anucleobase sequence comprising at least 9 contiguous nucleobases of anyof the nucleobase sequences of 8-2896. In certain embodiments, thecompound is an antisense compound or oligomeric compound. In certainembodiments, the compound is single-stranded. In certain embodiments,the compound is double-stranded. In certain embodiments, the modifiedoligonucleotide consists of 10 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 10 to 80 linked nucleosides and having anucleobase sequence comprising at least 10 contiguous nucleobases of anyof the nucleobase sequences of 8-2896. In certain embodiments, thecompound is an antisense compound or oligomeric compound. In certainembodiments, the compound is single-stranded. In certain embodiments,the compound is double-stranded. In certain embodiments, the modifiedoligonucleotide consists of 10 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 11 to 80 linked nucleosides and having anucleobase sequence comprising at least 11 contiguous nucleobases of anyof the nucleobase sequences of 8-2896. In certain embodiments, thecompound is an antisense compound or oligomeric compound. In certainembodiments, the compound is single-stranded. In certain embodiments,the compound is double-stranded. In certain embodiments, the modifiedoligonucleotide consists of 11 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 12 to 80 linked nucleosides and having anucleobase sequence comprising at least 12 contiguous nucleobases of anyof the nucleobase sequences of 8-2896. In certain embodiments, thecompound is an antisense compound or oligomeric compound. In certainembodiments, the compound is single-stranded. In certain embodiments,the compound is double-stranded. In certain embodiments, the modifiedoligonucleotide consists of 12 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 16 to 80 linked nucleosides and having anucleobase sequence comprising the nucleobase sequence of any one of8-2896. In certain embodiments, the compound is an antisense compound oroligomeric compound. In certain embodiments, the compound issingle-stranded. In certain embodiments, the compound isdouble-stranded. In certain embodiments, the modified oligonucleotideconsists of 16 to 30 linked nucleosides.

Certain embodiments provide a compound comprising a modifiedoligonucleotide having a nucleobase sequence consisting of thenucleobase sequence of any one of 8-2896. In certain embodiments, thecompound is an antisense compound or oligomeric compound. In certainembodiments, the compound is single-stranded. In certain embodiments,the compound is double-stranded.

Certain embodiments provide a compound comprising a modifiedoligonucleotide consisting of 12 to 30 linked nucleosides and having atleast an 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobaseportion complementary to an equal length portion within nucleobases3095-3369, 3371-7564, 7565-7672, 7673-8777, 8778-8909, 8910-10401,10402-10508, 10509-12040, 12041-12178, 12179-15641, 15642-15758,15759-20692, or 20693-22212 of SEQ ID NO: 2, wherein said modifiedoligonucleotide is at least 85%, at least 90%, at least 95%, or 100%complementary to SEQ ID NO: 2. In certain embodiments, the compound isan antisense compound or oligomeric compound. In certain embodiments,the compound is single-stranded. In certain embodiments, the compound isdouble-stranded. In certain embodiments, the modified oligonucleotideconsists of 10 to 30 linked nucleosides. In certain embodiments, themodified oligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having at least an 8, 9,10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portioncomplementary to an equal length portion within nucleobases 1-46,58-142, 1-142, 74-89, 154-197, 154-234, 200-232, 218-234, 240-345,254-269, 354-746, 354-830, 519-534, 565-580, 603-628, 693-716, 734-750,734-830, 749-828, 835-862, 835-957, 966-1044, 1017-1043, 1054-1106,1055-1070, 1075-1169, 1074-1132, 1136-1169, 1175-1218, 1180-1217,1250-1292, 1251-1279, 1296-1146, 1296-1448, 1308-1448, 1461-1481,1461-1519, 1461-1647, 1461-1646, 1483-1535, 1538-1646, 1544-1561,1597-1645, 1654-1685, 1654-1817, 1702-1817, 1705-1741, 1748-2211,2174-2219, 2240-2272, 2244-2272, 2349-2370, 2350-2371, or 2378-2394 ofan HSD17B13 nucleic acid having the nucleobase sequence of SEQ ID NO: 1.

In certain embodiments, a compound comprises a modified oligonucleotideconsisting of 8 to 80 linked nucleosides and having at least an 8, 9,10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portioncomplementary to an equal length portion within nucleobases 1-46,58-142, 1-142, 74-89, 154-197, 154-234, 200-232, 218-234, 240-345,254-269, 354-746, 354-830, 519-534, 565-580, 603-628, 693-716, 734-750,734-830, 749-828, 835-862, 835-957, 966-1044, 1017-1043, 1054-1106,1055-1070, 1075-1169, 1074-1132, 1136-1169, 1175-1218, 1180-1217,1250-1292, 1251-1279, 1296-1146, 1296-1448, 1308-1448, 1461-1481,1461-1519, 1461-1647, 1461-1646, 1483-1535, 1538-1646, 1544-1561,1597-1645, 1654-1685, 1654-1817, 1702-1817, 1705-1741, 1748-2211,2174-2219, 2240-2272, 2244-2272, 2349-2370, 2350-2371, or 2378-2394 ofan HSD17B13 nucleic acid having the nucleobase sequence of SEQ ID NO: 1.

In certain embodiments, compounds target within nucleobases 3095-3454,3095-3140, 3152-3236, 3168-3183, 3248-3328, 3312-3328, 3334-3390,3348-3390, 3401-3420, 3429-3451, 3429-3454, 3474-3719, 3474-3644,3478-3494, 3505-3531, 3544-3559, 3568-3634, 3671-3736, 3676-3717,3721-3799, 3741-3771, 3750-3770, 3782-3799, 3834-3849, 3834-4154,3877-3897, 3902-3917, 3933-3967, 3933-3979, 3988-4005, 3988-4017,4068-4091, 4103-4118, 4123-4155, 4133-4155, 4220-4240, 4220-4264,4249-4264, 4222-4240, 4296-4311, 4360-4378, 4389-4427, 4389-4431,4405-4449, 4476-4496, 4517-4588, 4517-4552, 4537-4552, 4572-4588,4640-4678, 4640-4879, 4641-4667, 4862-4879, 4991-5006, 4991-5305,5029-5098, 5046-5098, 5104-5120, 5121-5141, 5125-5141, 5156-5256,5158-5217, 5223-5242, 5267-5319, 5268-5319, 5395-5950, 5646-5695,5655-5858, 5712-5752, 5712-5777, 5758-5777, 5782-5797, 5782-5862,5804-5862, 5870-5910, 5871-6005, 5870-5910, 5870-5911, 5916-6007,5935-5950, 5974-6007, 6029-6048, 6029-6055, 6035-6164, 6084-6099,6084-6104, 6134-6164, 6170-6248, 6170-6275, 6170-6277, 6191-6218,6221-6243, 6246-6275, 6284-6350, 6284-6352, 6298-6372, 6357-6372,6388-6406, 6422-6493, 6422-6497, 6426-6621, 6567-6758, 6567-6582,6597-6653, 6626-6653, 6710-6779, 6784-6811, 6785-6800, 6795-6811,6913-6930, 6914-6929, 6914-6930, 6915-6930, 7101-7138, 7101-7441,7125-7145, 7426-7441, 7473-7494, 7473-7498, 7481-7498, 7526-7543,7550-7565, 7550-7634, 7563-7699, 7643-7676, 7680-7698, 7680-7699,7708-7723, 7751-7819, 7768-7796, 7828-7866, 7834-7969, 7938-7968,7938-7969, 7973-7994, 8017-8032, 8039-8186, 8039-8065, 8040-8065,8121-8156, 8125-8151, 8164-8185, 8164-8186, 8205-8297, 8205-8220,8236-8252, 8236-8271, 8256-8294, 8279-8297, 8487-8502, 8487-8627,8529-8579, 8587-8628, 8636-8732, 8643-8910, 8744-8762, 8786-8910,8939-9027, 8939-8996, 9000-9027, 9057-9096, 9080-9230, 9110-9173,9188-9240, 9256-9275, 9312-9365, 9372-9401, 9373-9394, 9410-9446,9410-9491, 9476-9555, 9497-9555, 9588-9678, 9588-9681, 9712-9737,9712-9742, 9751-9811, 9751-10040, 9887-9902, 9908-10017, 10025-10040,10058-10079, 10112-10160, 10124-10160, 10138-10160, 10180-10227,10180-10233, 10258-10279, 10292-10310, 10293-10310, 10335-10375,10335-10538, 10380-10538, 10554-10569, 10584-10599, 10728-10745,10831-10870, 10930-10946, 10931-10946, 10970-10993, 10971-11015,1100-11015, 11030-11045, 11073-11094, 11074-11094, 11115-11132,11117-11132, 11155-11171, 11210-11228, 11210-11276, 11235-11276,11290-11323, 11308-11323, 11384-11407, 11385-11443, 11428-11443,11468-11529, 11542-11605, 11621-11636, 11621-11638, 11621-11668,11652-11668, 11742-11808, 11742-11811, 11853-11881, 11853-11909,11892-11912, 11924-11940, 11925-12226, 11953-12027, 12038-12226,12238-12270, 12337-12531, 12337-12368, 12410-12448, 12465-12531,12598-12642, 12598-12742, 12647-12742, 12758-12832, 12761-12832,12862-12904, 13548-13627, 13551-13654, 13638-13674, 13688-13798,13704-13798, 13813-13932, 13949-14064, 13951-13969, 13975-14064,14077-14107, 14089-14107, 14126-14147, 14165-14221, 14166-14221,14243-14298, 14243-14299, 14315-14336, 14316-14336, 14362-14414,14432-14454, 14461-14514, 14465-14514, 14541-14815, 14541-14636,14724-14746, 1400-14815, 14905-14951, 14916-14951, 15019-15039,15022-15039, 15170-15185, 15200-15232, 15211-15268, 15244-15268,15279-15295, 15279-15399, 15312-15343, 15350-15399, 15405-15460,15492-15526, 15570-15586, 15633-15808, 15641-15657, 15643-15711,15716-15765, 15771-15802, 16116-16144, 16116-16149, 16189-16206,16189-16342, 16218-16240, 16254-16310, 16327-16352, 16377-16397,16377-16400, 16407-16439, 16407-16440, 16461-16476, 16533-16548,16755-16770, 16895-16920, 16905-16920, 16956-16984, 16956-17092,17014-17034, 17135-17159, 17041-17062, 17077-17092, 17135-17159,17227-17254, 17672-17795, 17675-17872, 17802-17817, 17857-17872,17909-17945, 17909-17971, 17953-17971, 17954-17971, 17984-18061,17985-18048, 18075-18117, 18087-18115, 18138-18160, 18176-18193,18505-18555, 18506-18536, 18585-18600, 18658-18712, 18662-18762,18720-18763, 18798-18864, 18871-18888, 18901-18940, 18925-18940,18958-18983, 18958-19013, 19388-19460, 19467-19513, 19474-19505,19531-19626, 19533-19626, 19649-19717, 19649-19726, 19731-19801,19731-19842, 19815-19875, 19860-19951, 19887-19951, 19970-19985,19970-20054, 19999-20024, 20037-20061, 20087-20102, 20109-20153,20087-20207, 20172-20212, 20356-20438, 20248-20437, 20248-20264,20470-20508, 20481-20507, 20571-20623, 20571-20644, 20685-20700,20706-21032, 20706-20772, 20781-20859, 20869-20984, 20990-21033,21065-21102, 21065-21263, 21092-21632, 21276-21500, 21517-21632,21989-22034, 22059-22087, or 22164-22209 of an HSD17B13 nucleic acidhaving the nucleobase sequence of SEQ ID NO: 2.

In certain embodiments, compounds have at least an 8, 9, 10, 11, 12, 13,14, 15, or 16 contiguous nucleobase portion complementary to an equallength portion within nucleobases 3095-3454, 3095-3140, 3152-3236,3168-3183, 3248-3328, 3312-3328, 3334-3390, 3348-3390, 3401-3420,3429-3451, 3429-3454, 3474-3719, 3474-3644, 3478-3494, 3505-3531,3544-3559, 3568-3634, 3671-3736, 3676-3717, 3721-3799, 3741-3771,3750-3770, 3782-3799, 3834-3849, 3834-4154, 3877-3897, 3902-3917,3933-3967, 3933-3979, 3988-4005, 3988-4017, 4068-4091, 4103-4118,4123-4155, 4133-4155, 4220-4240, 4220-4264, 4249-4264, 4222-4240,4296-4311, 4360-4378, 4389-4427, 4389-4431, 4405-4449, 4476-4496,4517-4588, 4517-4552, 4537-4552, 4572-4588, 4640-4678, 4640-4879,4641-4667, 4862-4879, 4991-5006, 4991-5305, 5029-5098, 5046-5098,5104-5120, 5121-5141, 5125-5141, 5156-5256, 5158-5217, 5223-5242,5267-5319, 5268-5319, 5395-5950, 5646-5695, 5655-5858, 5712-5752,5712-5777, 5758-5777, 5782-5797, 5782-5862, 5804-5862, 5870-5910,5871-6005, 5870-5910, 5870-5911, 5916-6007, 5935-5950, 5974-6007,6029-6048, 6029-6055, 6035-6164, 6084-6099, 6084-6104, 6134-6164,6170-6248, 6170-6275, 6170-6277, 6191-6218, 6221-6243, 6246-6275,6284-6350, 6284-6352, 6298-6372, 6357-6372, 6388-6406, 6422-6493,6422-6497, 6426-6621, 6567-6758, 6567-6582, 6597-6653, 6626-6653,6710-6779, 6784-6811, 6785-6800, 6795-6811, 6913-6930, 6914-6929,6914-6930, 6915-6930, 7101-7138, 7101-7441, 7125-7145, 7426-7441,7473-7494, 7473-7498, 7481-7498, 7526-7543, 7550-7565, 7550-7634,7563-7699, 7643-7676, 7680-7698, 7680-7699, 7708-7723, 7751-7819,7768-7796, 7828-7866, 7834-7969, 7938-7968, 7938-7969, 7973-7994,8017-8032, 8039-8186, 8039-8065, 8040-8065, 8121-8156, 8125-8151,8164-8185, 8164-8186, 8205-8297, 8205-8220, 8236-8252, 8236-8271,8256-8294, 8279-8297, 8487-8502, 8487-8627, 8529-8579, 8587-8628,8636-8732, 8643-8910, 8744-8762, 8786-8910, 8939-9027, 8939-8996,9000-9027, 9057-9096, 9080-9230, 9110-9173, 9188-9240, 9256-9275,9312-9365, 9372-9401, 9373-9394, 9410-9446, 9410-9491, 9476-9555,9497-9555, 9588-9678, 9588-9681, 9712-9737, 9712-9742, 9751-9811,9751-10040, 9887-9902, 9908-10017, 10025-10040, 10058-10079,10112-10160, 10124-10160, 10138-10160, 10180-10227, 10180-10233,10258-10279, 10292-10310, 10293-10310, 10335-10375, 10335-10538,10380-10538, 10554-10569, 10584-10599, 10728-10745, 10831-10870,10930-10946, 10931-10946, 10970-10993, 10971-11015, 1100-11015,11030-11045, 11073-11094, 11074-11094, 11115-11132, 11117-11132,11155-11171, 11210-11228, 11210-11276, 11235-11276, 11290-11323,11308-11323, 11384-11407, 11385-11443, 11428-11443, 11468-11529,11542-11605, 11621-11636, 11621-11638, 11621-11668, 11652-11668,11742-11808, 11742-11811, 11853-11881, 11853-11909, 11892-11912,11924-11940, 11925-12226, 11953-12027, 12038-12226, 12238-12270,12337-12531, 12337-12368, 12410-12448, 12465-12531, 12598-12642,12598-12742, 12647-12742, 12758-12832, 12761-12832, 12862-12904,13548-13627, 13551-13654, 13638-13674, 13688-13798, 13704-13798,13813-13932, 13949-14064, 13951-13969, 13975-14064, 14077-14107,14089-14107, 14126-14147, 14165-14221, 14166-14221, 14243-14298,14243-14299, 14315-14336, 14316-14336, 14362-14414, 14432-14454,14461-14514, 14465-14514, 14541-14815, 14541-14636, 14724-14746,1400-14815, 14905-14951, 14916-14951, 15019-15039, 15022-15039,15170-15185, 15200-15232, 15211-15268, 15244-15268, 15279-15295,15279-15399, 15312-15343, 15350-15399, 15405-15460, 15492-15526,15570-15586, 15633-15808, 15641-15657, 15643-15711, 15716-15765,15771-15802, 16116-16144, 16116-16149, 16189-16206, 16189-16342,16218-16240, 16254-16310, 16327-16352, 16377-16397, 16377-16400,16407-16439, 16407-16440, 16461-16476, 16533-16548, 16755-16770,16895-16920, 16905-16920, 16956-16984, 16956-17092, 17014-17034,17135-17159, 17041-17062, 17077-17092, 17135-17159, 17227-17254,17672-17795, 17675-17872, 17802-17817, 17857-17872, 17909-17945,17909-17971, 17953-17971, 17954-17971, 17984-18061, 17985-18048,18075-18117, 18087-18115, 18138-18160, 18176-18193, 18505-18555,18506-18536, 18585-18600, 18658-18712, 18662-18762, 18720-18763,18798-18864, 18871-18888, 18901-18940, 18925-18940, 18958-18983,18958-19013, 19388-19460, 19467-19513, 19474-19505, 19531-19626,19533-19626, 19649-19717, 19649-19726, 19731-19801, 19731-19842,19815-19875, 19860-19951, 19887-19951, 19970-19985, 19970-20054,19999-20024, 20037-20061, 20087-20102, 20109-20153, 20087-20207,20172-20212, 20356-20438, 20248-20437, 20248-20264, 20470-20508,20481-20507, 20571-20623, 20571-20644, 20685-20700, 20706-21032,20706-20772, 20781-20859, 20869-20984, 20990-21033, 21065-21102,21065-21263, 21092-21632, 21276-21500, 21517-21632, 21989-22034,22059-22087, or 22164-22209 of an HSD17B13 nucleic acid having thenucleobase sequence of SEQ ID NO: 2. In certain embodiments, thesecompounds are antisense compounds, oligomeric compounds, oroligonucleotides. In certain embodiments, the modified oligonucleotideconsists of 10 to 30 linked nucleosides. In certain embodiments, themodified oligonucleotide consists of 16 to 30 linked nucleosides.

In certain embodiments, compounds have a nucleobase sequencecomplementary to nucleobases 1323-1338, 1600-1615, 1627-1642, or1782-1797 of an HSD17B13 nucleic acid having the nucleobase sequence ofSEQ ID NO: 1.

In certain embodiments, compounds have a nucleobase sequence comprisinga portion of at least 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguousnucleobases complementary within an equal length portion of nucleobases1323-1338, 1600-1615, 1627-1642, or 1782-1797 of an HSD17B13 nucleicacid having the nucleobase sequence of SEQ ID NO: 1. In certainembodiments, these compounds are antisense compounds, oligomericcompounds, or oligonucleotides. In certain embodiments, the modifiedoligonucleotide consists of 10 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 to 30 linkednucleosides.

In certain embodiments, compounds have a nucleobase sequencecomplementary to nucleobases 3439-3454, 3552-3567, 3754-3769, 3963-3978,4406-4421, 4123-4138, 4139-4154, 4991-5006, 5045-5060, 5662-5677,6476-6491, 6478-6493, 17992-18007, 21138-21153, 21415-21430,21442-21457, or 21597-21612 of an HSD17B13 nucleic acid having thenucleobase sequence of SEQ ID NO: 2.

In certain embodiments, compounds have a nucleobase sequence comprisinga portion of at least 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguousnucleobases complementary within an equal length portion of nucleobases3439-3454, 3552-3567, 3754-3769, 3963-3978, 4406-4421, 4123-4138,4139-4154, 4991-5006, 5045-5060, 5662-5677, 6476-6491, 6478-6493,17992-18007, 21138-21153, 21415-21430, 21442-21457, or 21597-21612 of anHSD17B13 nucleic acid having the nucleobase sequence of SEQ ID NO: 2. Incertain embodiments, these compounds are antisense compounds, oligomericcompounds, or oligonucleotides. In certain embodiments, the modifiedoligonucleotide consists of 10 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 to 30 linkednucleosides.

In certain embodiments, any of the foregoing modified oligonucleotideshas at least one modified internucleoside linkage, at least one modifiedsugar, and/or at least one modified nucleobase.

In certain embodiments, at least one nucleoside of any of the foregoingmodified oligonucleotides comprises a modified sugar. In certainembodiments, the modified sugar comprises a 2′-O-methoxyethyl group. Incertain embodiments, the modified sugar is a bicyclic sugar, such as a4′-CH(CH3)-O-2′ group, a 4′-CH2-O-2′ group, or a 4′-(CH2)2-O-2′group.

In certain embodiments, at least one internucleoside linkage of themodified oligonucleotide comprises a modified internucleoside linkage,such as a phosphorothioate internucleoside linkage.

In certain embodiments, at least one nucleobase of any of the foregoingmodified oligonucleotides comprises a modified nucleobase, such as5-methylcytosine.

In certain embodiments, any of the foregoing modified oligonucleotideshas:

-   -   a gap segment consisting of linked deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;        wherein the gap segment is positioned between the 5′ wing        segment and the 3′ wing segment and wherein each nucleoside of        each wing segment comprises a modified sugar. In certain        embodiments, the modified oligonucleotide consists of 12 to 30        linked nucleosides and has a nucleobase sequence comprising the        sequence recited in any one of SEQ ID NOs: 8-2896. In certain        embodiments, the modified oligonucleotide is 16 to 30 linked        nucleosides in length having a nucleobase sequence comprising        the nucleobase sequence recited in any one of SEQ ID NOs:        8-2896. In certain embodiments, the modified oligonucleotide is        16 linked nucleosides in length having a nucleobase sequence        consisting of the sequence recited in any one of SEQ ID NOs:        8-2896.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide consisting of 16 to 80 linked nucleobases and having anucleobase sequence comprising the nucleobase sequence recited in anyone of 8-2896, wherein the modified oligonucleotide has:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar. In certain embodiments, the modifiedoligonucleotide consists of 16 to 30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide 12-30 linked nucleobases in length having a nucleobasesequence comprising the sequence recited in any one of SEQ ID NOs: 286,817, 983, 1215, 747, 43, 355, 1602, 201, 734, 1249, 208, 513, 1449,1448, and 1595, wherein the modified oligonucleotide has:

a gap segment consisting of ten linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment, wherein each nucleoside of each wing segmentcomprises a cEt sugar; wherein each internucleoside linkage is aphosphorothioate linkage and wherein each cytosine is a5-methylcytosine. In certain embodiments, the modified oligonucleotideconsists of 16-30 linked nucleosides. In certain embodiments, themodified oligonucleotide consists of 16 linked nucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide 12-30 linked nucleobases in length having a nucleobasesequence comprising the sequence recited in any one of SEQ ID NOs: 819,wherein the modified oligonucleotide has:

a gap segment consisting of nine linked 2′-deoxynucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment, wherein each nucleoside of the 5′ wing segmentcomprises a cEt sugar; wherein the sugar residues of the nucleosides ofthe 3′ wing segment are 5′-cEt-cEt-cEt-MOE-3′; wherein eachinternucleoside linkage is a phosphorothioate linkage and wherein eachcytosine is a 5-methylcytosine. In certain embodiments, the modifiedoligonucleotide consists of 16-30 linked nucleosides. In certainembodiments, the modified oligonucleotide consists of 16 linkednucleosides.

In certain embodiments, a compound comprises or consists of a modifiedoligonucleotide 12-30 linked nucleobases in length having a nucleobasesequence comprising the sequence recited in any one of SEQ ID NOs: 1595,wherein the modified oligonucleotide has:

a gap segment consisting of ten linked nucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein the gap segment consists of 5′-onedeoxy, one 2′-O-methyl nucleoside, and eight deoxynucleosides-3′,wherein each nucleoside of each of the wing segments comprises a cEtsugar; wherein each internucleoside linkage is a phosphorothioatelinkage and wherein each cytosine is a 5-methylcytosine. In certainembodiments, the modified oligonucleotide consists of 16-30 linkednucleosides. In certain embodiments, the modified oligonucleotideconsists of 16 linked nucleosides.

In any of the foregoing embodiments, the compound or oligonucleotide canbe at least 85%, at least 90%, at least 95%, at least 98%, at least 99%,or 100% complementary to a nucleic acid encoding HSD17B13.

In any of the foregoing embodiments, the compound can besingle-stranded. In certain embodiments, the compound comprisesdeoxyribonucleotides. In certain embodiments, the compound isdouble-stranded. In certain embodiments, the compound is double-strandedand comprises ribonucleotides. In any of the foregoing embodiments, thecompound can be an antisense compound or oligomeric compound.

In any of the foregoing embodiments, the compound can consist of 8 to80, 10 to 30, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to30, 15 to 50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 22, 18 to24, 18 to 30, 18 to 50, 19 to 22, 19 to 30, 19 to 50, or 20 to 30 linkednucleosides. In certain embodiments, the compound comprises or consistsof an oligonucleotide.

In certain embodiments, a compound comprises a modified oligonucleotidedescribed herein and a conjugate group. In certain embodiments, theconjugate group is linked to the modified oligonucleotide at the 5′ endof the modified oligonucleotide. In certain embodiments, the conjugategroup is linked to the modified oligonucleotide at the 3′ end of themodified oligonucleotide. In certain embodiments, the conjugate groupcomprises at least one N-Acetylgalactosamine (GalNAc), at least twoN-Acetylgalactosamines (GalNAcs), or at least threeN-Acetylgalactosamines (GalNAcs).

In certain embodiments, compounds or compositions provided hereincomprise a pharmaceutically acceptable salt of the modifiedoligonucleotide. In certain embodiments, the salt is a sodium salt. Incertain embodiments, the salt is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

or a salt thereof. In certain embodiments, the compound is a sodiumsalt. In certain embodiments, the compound is a potassium salt.

In certain embodiments, a compound provided herein is according to thefollowing chemical structure:

Under certain conditions, certain compounds disclosed herein act asacids. Although such compounds may be drawn or described in protonated(free acid) form, or ionized and in association with a cation (salt)form, aqueous solutions of such compounds exist in equilibrium amongsuch forms. For example, a phosphate linkage of an oligonucleotide inaqueous solution exists in equilibrium among free acid, anion and saltforms. Unless otherwise indicated, compounds described herein areintended to include all such forms. Moreover, certain oligonucleotideshave several such linkages, each of which is in equilibrium. Thus,oligonucleotides in solution exist in an ensemble of forms at multiplepositions all at equilibrium. The term “oligonucleotide” is intended toinclude all such forms. Drawn structures necessarily depict a singleform. Nevertheless, unless otherwise indicated, such drawings arelikewise intended to include corresponding forms. Herein, a structuredepicting the free acid of a compound followed by the term “or a saltthereof” expressly includes all such forms that may be fully orpartially protonated/de-protonated/in association with a cation. Incertain instances, one or more specific cation is identified.

In certain embodiments, modified oligonucleotides or oligomericcompounds are in aqueous solution with sodium. In certain embodiments,modified oligonucleotides or oligomeric compounds are in aqueoussolution with potassium. In certain embodiments, modifiedoligonucleotides or oligomeric compounds are in PBS. In certainembodiments, modified oligonucleotides or oligomeric compounds are inwater. In certain such embodiments, the pH of the solution is adjustedwith NaOH and/or HCl to achieve a desired pH. In certain embodiments,the compounds or compositions as described herein are active by virtueof having at least one of an in vitro IC₅₀ of less than 2 μM, less than1.5 μM, less than 1 μM, less than 0.9 μM, less than 0.8 μM, less than0.7 μM, less than 0.6 μM, less than 0.5 μM, less than 0.4 μM, less than0.3 μM, less than 0.2 μM, less than 0.1 μM, less than 0.05 μM, less than0.04 μM, less than 0.03 μM, less than 0.02 μM, or less than 0.01 μM.

In certain embodiments, the compounds or compositions as describedherein are highly tolerable as demonstrated by having at least one of anincrease in alanine transaminase (ALT) or aspartate transaminase (AST)value of no more than 4 fold, 3 fold, or 2 fold over control animals, oran increase in liver, spleen, or kidney weight of no more than 30%, 20%,15%, 12%, 10%, 5%, or 2% compared to control animals. In certainembodiments, the compounds or compositions as described herein arehighly tolerable as demonstrated by having no increase of ALT or ASTover control animals. In certain embodiments, the compounds orcompositions as described herein are highly tolerable as demonstrated byhaving no increase in liver, spleen, or kidney weight over controlanimals.

Certain embodiments provide a composition comprising the compound of anyof the aforementioned embodiments or any pharmaceutically acceptablesalt thereof and at least one of a pharmaceutically acceptable carrieror diluent. In certain embodiments, the composition has a viscosity lessthan about 40 centipoise (cP), less than about 30 centipose (cP), lessthan about 20 centipose (cP), less than about 15 centipose (cP), or lessthan about 10 centipose (cP). In certain embodiments, the compositionhaving any of the aforementioned viscosities comprises a compoundprovided herein at a concentration of about 100 mg/mL, about 125 mg/mL,about 150 mg/mL, about 175 mg/mL, about 200 mg/mL, about 225 mg/mL,about 250 mg/mL, about 275 mg/mL, or about 300 mg/mL. In certainembodiments, the composition having any of the aforementionedviscosities and/or compound concentrations has a temperature of roomtemperature, or about 20° C., about 21° C., about 22° C., about 23° C.,about 24° C., about 25° C., about 26° C., about 27° C., about 28° C.,about 29° C., or about 30° C.

Non-limiting numbered embodiments include:

Embodiment 1: Certain embodiments provide a compound comprising amodified oligonucleotide consisting of 8 to 80 linked nucleosides andhaving a nucleobase sequence comprising at least 8, at least 9, at least10, at least 11, or at least 12 contiguous nucleobases of any of thenucleobase sequences of SEQ ID NOs: 8-2896. Certain embodiments providea compound comprising a modified oligonucleotide consisting of 12 to 30linked nucleosides, wherein wherein the modified oligonucleotide has anucleobase sequence comprising at least 8, at least 9, at least 10, atleast 11, or at least 12 contiguous nucleobases of any of the nucleobasesequences of SEQ ID NOs: 8-2896.

Embodiment 2: Certain embodiments provide a compound comprising modifiedoligonucleotide consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising the nucleobase sequence of any one of SEQID NOs: 8-2896. Certain embodiments provide a compound comprisingmodified oligonucleotide consisting of 12 to 30 linked nucleosides andhaving a nucleobase sequence comprising the nucleobase sequence of anyone of SEQ ID NOs: 8-2896.

Embodiment 3: Certain embodiments provide a compound comprising amodified oligonucleotide having a nucleobase sequence consisting of anyone of SEQ ID NOs: 8-2896.

Embodiment 4: Certain embodiments provide a compound comprising modifiedoligonucleotide consisting of 8 to 80 linked nucleosides, or consistingof 12 to 30 linked nucleosides, wherein the modified oligonucleotide hasa nucleobase sequence comprising a portion of at least 8 contiguousnucleobases complementary to an equal length portion of nucleobases3095-3454, 3095-3140, 3152-3236, 3168-3183, 3248-3328, 3312-3328,3334-3390, 3348-3390, 3401-3420, 3429-3451, 3429-3454, 3474-3719,3474-3644, 3478-3494, 3505-3531, 3544-3559, 3568-3634, 3671-3736,3676-3717, 3721-3799, 3741-3771, 3750-3770, 3782-3799, 3834-3849,3834-4154, 3877-3897, 3902-3917, 3933-3967, 3933-3979, 3988-4005,3988-4017, 4068-4091, 4103-4118, 4123-4155, 4133-4155, 4220-4240,4220-4264, 4249-4264, 4222-4240, 4296-4311, 4360-4378, 4389-4427,4389-4431, 4405-4449, 4476-4496, 4517-4588, 4517-4552, 4537-4552,4572-4588, 4640-4678, 4640-4879, 4641-4667, 4862-4879, 4991-5006,4991-5305, 5029-5098, 5046-5098, 5104-5120, 5121-5141, 5125-5141,5156-5256, 5158-5217, 5223-5242, 5267-5319, 5268-5319, 5395-5950,5646-5695, 5655-5858, 5712-5752, 5712-5777, 5758-5777, 5782-5797,5782-5862, 5804-5862, 5870-5910, 5871-6005, 5870-5910, 5870-5911,5916-6007, 5935-5950, 5974-6007, 6029-6048, 6029-6055, 6035-6164,6084-6099, 6084-6104, 6134-6164, 6170-6248, 6170-6275, 6170-6277,6191-6218, 6221-6243, 6246-6275, 6284-6350, 6284-6352, 6298-6372,6357-6372, 6388-6406, 6422-6493, 6422-6497, 6426-6621, 6567-6758,6567-6582, 6597-6653, 6626-6653, 6710-6779, 6784-6811, 6785-6800,6795-6811, 6913-6930, 6914-6929, 6914-6930, 6915-6930, 7101-7138,7101-7441, 7125-7145, 7426-7441, 7473-7494, 7473-7498, 7481-7498,7526-7543, 7550-7565, 7550-7634, 7563-7699, 7643-7676, 7680-7698,7680-7699, 7708-7723, 7751-7819, 7768-7796, 7828-7866, 7834-7969,7938-7968, 7938-7969, 7973-7994, 8017-8032, 8039-8186, 8039-8065,8040-8065, 8121-8156, 8125-8151, 8164-8185, 8164-8186, 8205-8297,8205-8220, 8236-8252, 8236-8271, 8256-8294, 8279-8297, 8487-8502,8487-8627, 8529-8579, 8587-8628, 8636-8732, 8643-8910, 8744-8762,8786-8910, 8939-9027, 8939-8996, 9000-9027, 9057-9096, 9080-9230,9110-9173, 9188-9240, 9256-9275, 9312-9365, 9372-9401, 9373-9394,9410-9446, 9410-9491, 9476-9555, 9497-9555, 9588-9678, 9588-9681,9712-9737, 9712-9742, 9751-9811, 9751-10040, 9887-9902, 9908-10017,10025-10040, 10058-10079, 10112-10160, 10124-10160, 10138-10160,10180-10227, 10180-10233, 10258-10279, 10292-10310, 10293-10310,10335-10375, 10335-10538, 10380-10538, 10554-10569, 10584-10599,10728-10745, 10831-10870, 10930-10946, 10931-10946, 10970-10993,10971-11015, 1100-11015, 11030-11045, 11073-11094, 11074-11094,11115-11132, 11117-11132, 11155-11171, 11210-11228, 11210-11276,11235-11276, 11290-11323, 11308-11323, 11384-11407, 11385-11443,11428-11443, 11468-11529, 11542-11605, 11621-11636, 11621-11638,11621-11668, 11652-11668, 11742-11808, 11742-11811, 11853-11881,11853-11909, 11892-11912, 11924-11940, 11925-12226, 11953-12027,12038-12226, 12238-12270, 12337-12531, 12337-12368, 12410-12448,12465-12531, 12598-12642, 12598-12742, 12647-12742, 12758-12832,12761-12832, 12862-12904, 13548-13627, 13551-13654, 13638-13674,13688-13798, 13704-13798, 13813-13932, 13949-14064, 13951-13969,13975-14064, 14077-14107, 14089-14107, 14126-14147, 14165-14221,14166-14221, 14243-14298, 14243-14299, 14315-14336, 14316-14336,14362-14414, 14432-14454, 14461-14514, 14465-14514, 14541-14815,14541-14636, 14724-14746, 1400-14815, 14905-14951, 14916-14951,15019-15039, 15022-15039, 15170-15185, 15200-15232, 15211-15268,15244-15268, 15279-15295, 15279-15399, 15312-15343, 15350-15399,15405-15460, 15492-15526, 15570-15586, 15633-15808, 15641-15657,15643-15711, 15716-15765, 15771-15802, 16116-16144, 16116-16149,16189-16206, 16189-16342, 16218-16240, 16254-16310, 16327-16352,16377-16397, 16377-16400, 16407-16439, 16407-16440, 16461-16476,16533-16548, 16755-16770, 16895-16920, 16905-16920, 16956-16984,16956-17092, 17014-17034, 17135-17159, 17041-17062, 17077-17092,17135-17159, 17227-17254, 17672-17795, 17675-17872, 17802-17817,17857-17872, 17909-17945, 17909-17971, 17953-17971, 17954-17971,17984-18061, 17985-18048, 18075-18117, 18087-18115, 18138-18160,18176-18193, 18505-18555, 18506-18536, 18585-18600, 18658-18712,18662-18762, 18720-18763, 18798-18864, 18871-18888, 18901-18940,18925-18940, 18958-18983, 18958-19013, 19388-19460, 19467-19513,19474-19505, 19531-19626, 19533-19626, 19649-19717, 19649-19726,19731-19801, 19731-19842, 19815-19875, 19860-19951, 19887-19951,19970-19985, 19970-20054, 19999-20024, 20037-20061, 20087-20102,20109-20153, 20087-20207, 20172-20212, 20356-20438, 20248-20437,20248-20264, 20470-20508, 20481-20507, 20571-20623, 20571-20644,20685-20700, 20706-21032, 20706-20772, 20781-20859, 20869-20984,20990-21033, 21065-21102, 21065-21263, 21092-21632, 21276-21500,21517-21632, 21989-22034, 22059-22087, or 22164-22209 of SEQ ID NO: 2,and wherein the nucleobase sequence of the modified oligonucleotide isat least 85%, at least 90%, at least 95%, or 100% complementary to SEQID NO: 2.

Embodiment 5: Certain embodiments provide a compound comprising amodified oligonucleotide consisting of 8 to 80 linked nucleosides,wherein the modified oligonucleotide has a nucleobase sequencecomplementary within nucleobases 3095-3454, 3095-3140, 3152-3236,3168-3183, 3248-3328, 3312-3328, 3334-3390, 3348-3390, 3401-3420,3429-3451, 3429-3454, 3474-3719, 3474-3644, 3478-3494, 3505-3531,3544-3559, 3568-3634, 3671-3736, 3676-3717, 3721-3799, 3741-3771,3750-3770, 3782-3799, 3834-3849, 3834-4154, 3877-3897, 3902-3917,3933-3967, 3933-3979, 3988-4005, 3988-4017, 4068-4091, 4103-4118,4123-4155, 4133-4155, 4220-4240, 4220-4264, 4249-4264, 4222-4240,4296-4311, 4360-4378, 4389-4427, 4389-4431, 4405-4449, 4476-4496,4517-4588, 4517-4552, 4537-4552, 4572-4588, 4640-4678, 4640-4879,4641-4667, 4862-4879, 4991-5006, 4991-5305, 5029-5098, 5046-5098,5104-5120, 5121-5141, 5125-5141, 5156-5256, 5158-5217, 5223-5242,5267-5319, 5268-5319, 5395-5950, 5646-5695, 5655-5858, 5712-5752,5712-5777, 5758-5777, 5782-5797, 5782-5862, 5804-5862, 5870-5910,5871-6005, 5870-5910, 5870-5911, 5916-6007, 5935-5950, 5974-6007,6029-6048, 6029-6055, 6035-6164, 6084-6099, 6084-6104, 6134-6164,6170-6248, 6170-6275, 6170-6277, 6191-6218, 6221-6243, 6246-6275,6284-6350, 6284-6352, 6298-6372, 6357-6372, 6388-6406, 6422-6493,6422-6497, 6426-6621, 6567-6758, 6567-6582, 6597-6653, 6626-6653,6710-6779, 6784-6811, 6785-6800, 6795-6811, 6913-6930, 6914-6929,6914-6930, 6915-6930, 7101-7138, 7101-7441, 7125-7145, 7426-7441,7473-7494, 7473-7498, 7481-7498, 7526-7543, 7550-7565, 7550-7634,7563-7699, 7643-7676, 7680-7698, 7680-7699, 7708-7723, 7751-7819,7768-7796, 7828-7866, 7834-7969, 7938-7968, 7938-7969, 7973-7994,8017-8032, 8039-8186, 8039-8065, 8040-8065, 8121-8156, 8125-8151,8164-8185, 8164-8186, 8205-8297, 8205-8220, 8236-8252, 8236-8271,8256-8294, 8279-8297, 8487-8502, 8487-8627, 8529-8579, 8587-8628,8636-8732, 8643-8910, 8744-8762, 8786-8910, 8939-9027, 8939-8996,9000-9027, 9057-9096, 9080-9230, 9110-9173, 9188-9240, 9256-9275,9312-9365, 9372-9401, 9373-9394, 9410-9446, 9410-9491, 9476-9555,9497-9555, 9588-9678, 9588-9681, 9712-9737, 9712-9742, 9751-9811,9751-10040, 9887-9902, 9908-10017, 10025-10040, 10058-10079,10112-10160, 10124-10160, 10138-10160, 10180-10227, 10180-10233,10258-10279, 10292-10310, 10293-10310, 10335-10375, 10335-10538,10380-10538, 10554-10569, 10584-10599, 10728-10745, 10831-10870,10930-10946, 10931-10946, 10970-10993, 10971-11015, 1100-11015,11030-11045, 11073-11094, 11074-11094, 11115-11132, 11117-11132,11155-11171, 11210-11228, 11210-11276, 11235-11276, 11290-11323,11308-11323, 11384-11407, 11385-11443, 11428-11443, 11468-11529,11542-11605, 11621-11636, 11621-11638, 11621-11668, 11652-11668,11742-11808, 11742-11811, 11853-11881, 11853-11909, 11892-11912,11924-11940, 11925-12226, 11953-12027, 12038-12226, 12238-12270,12337-12531, 12337-12368, 12410-12448, 12465-12531, 12598-12642,12598-12742, 12647-12742, 12758-12832, 12761-12832, 12862-12904,13548-13627, 13551-13654, 13638-13674, 13688-13798, 13704-13798,13813-13932, 13949-14064, 13951-13969, 13975-14064, 14077-14107,14089-14107, 14126-14147, 14165-14221, 14166-14221, 14243-14298,14243-14299, 14315-14336, 14316-14336, 14362-14414, 14432-14454,14461-14514, 14465-14514, 14541-14815, 14541-14636, 14724-14746,1400-14815, 14905-14951, 14916-14951, 15019-15039, 15022-15039,15170-15185, 15200-15232, 15211-15268, 15244-15268, 15279-15295,15279-15399, 15312-15343, 15350-15399, 15405-15460, 15492-15526,15570-15586, 15633-15808, 15641-15657, 15643-15711, 15716-15765,15771-15802, 16116-16144, 16116-16149, 16189-16206, 16189-16342,16218-16240, 16254-16310, 16327-16352, 16377-16397, 16377-16400,16407-16439, 16407-16440, 16461-16476, 16533-16548, 16755-16770,16895-16920, 16905-16920, 16956-16984, 16956-17092, 17014-17034,17135-17159, 17041-17062, 17077-17092, 17135-17159, 17227-17254,17672-17795, 17675-17872, 17802-17817, 17857-17872, 17909-17945,17909-17971, 17953-17971, 17954-17971, 17984-18061, 17985-18048,18075-18117, 18087-18115, 18138-18160, 18176-18193, 18505-18555,18506-18536, 18585-18600, 18658-18712, 18662-18762, 18720-18763,18798-18864, 18871-18888, 18901-18940, 18925-18940, 18958-18983,18958-19013, 19388-19460, 19467-19513, 19474-19505, 19531-19626,19533-19626, 19649-19717, 19649-19726, 19731-19801, 19731-19842,19815-19875, 19860-19951, 19887-19951, 19970-19985, 19970-20054,19999-20024, 20037-20061, 20087-20102, 20109-20153, 20087-20207,20172-20212, 20356-20438, 20248-20437, 20248-20264, 20470-20508,20481-20507, 20571-20623, 20571-20644, 20685-20700, 20706-21032,20706-20772, 20781-20859, 20869-20984, 20990-21033, 21065-21102,21065-21263, 21092-21632, 21276-21500, 21517-21632, 21989-22034,22059-22087, or 22164-22209 of SEQ ID NO: 2, and wherein said modifiedoligonucleotide is at least 85%, at least 90%, at least 95%, or 100%complementary to SEQ ID NO: 2.

Embodiment 6: Certain embodiments provide a compound comprising amodified oligonucleotide consisting of 8 to 80 linked nucleosides,wherein the modified oligonucleotide has a nucleobase sequencecomprising a portion of at least 8 contiguous nucleobases 100%complementary to an equal length portion of nucleobases 1-46, 58-142,1-142, 74-89, 154-197, 154-234, 200-232, 218-234, 240-345, 254-269,354-746, 354-830, 519-534, 565-580, 603-628, 693-716, 734-750, 734-830,749-828, 835-862, 835-957, 966-1044, 1017-1043, 1054-1106, 1055-1070,1075-1169, 1074-1132, 1136-1169, 1175-1218, 1180-1217, 1250-1292,1251-1279, 1296-1146, 1296-1448, 1308-1448, 1461-1481, 1461-1519,1461-1647, 1461-1646, 1483-1535, 1538-1646, 1544-1561, 1597-1645,1654-1685, 1654-1817, 1702-1817, 1705-1741, 1748-2211, 2174-2219,2240-2272, 2244-2272, 2349-2370, 2350-2371, or 2378-2394 of SEQ ID NO:1, and wherein the nucleobase sequence of the modified oligonucleotideis at least 85%, at least 90%, at least 95%, or 100% complementary toSEQ ID NO: 1.

Embodiment 7: Certain embodiments provide a compound comprising amodified oligonucleotide consisting of 8 to 80 linked nucleosides,wherein the modified oligonucleotide has a nucleobase sequencecomplementary within nucleobases 1-46, 58-142, 1-142, 74-89, 154-197,154-234, 200-232, 218-234, 240-345, 254-269, 354-746, 354-830, 519-534,565-580, 603-628, 693-716, 734-750, 734-830, 749-828, 835-862, 835-957,966-1044, 1017-1043, 1054-1106, 1055-1070, 1075-1169, 1074-1132,1136-1169, 1175-1218, 1180-1217, 1250-1292, 1251-1279, 1296-1146,1296-1448, 1308-1448, 1461-1481, 1461-1519, 1461-1647, 1461-1646,1483-1535, 1538-1646, 1544-1561, 1597-1645, 1654-1685, 1654-1817,1702-1817, 1705-1741, 1748-2211, 2174-2219, 2240-2272, 2244-2272,2349-2370, 2350-2371, or 2378-2394 of SEQ ID NO: 1, and wherein saidmodified oligonucleotide is at least 85%, at least 90%, at least 95%, or100% complementary to SEQ ID NO: 1.

Embodiment 8: Certain embodiments provide a compound comprising amodified oligonucleotide consisting of 12 to 30 linked nucleosides,wherein the modified oligonucleotide has a nucleobase sequencecomprising a portion of at least 8, at least 9, at least 10, at least11, at least 12, at least 13, at least 14, at least 15, at least 16contiguous nucleobases 100% complementary to an equal length portion ofnucleobases 3439-3454, 3552-3567, 3754-3769, 3963-3978, 4406-4421,4123-4138, 4139-4154, 4991-5006, 5045-5060, 5662-5677, 6476-6491,6478-6493, 17992-18007, 21138-21153, 21415-21430, 21442-21457, or21597-21612 of SEQ ID NO: 2, and wherein the nucleobase sequence of themodified oligonucleotide is at least 85%, at least 90%, at least 95%, or100% complementary to SEQ ID NO: 2.

Embodiment 9: Certain embodiments provide a compound comprising amodified oligonucleotide consisting of 12 to 30 linked nucleosides,wherein the modified oligonucleotide has a nucleobase sequencecomprising any one of SEQ ID NOs: 286, 817, 983, 1215, 747, 43, 355,1602, 201, 734, 1249, 208, 513, 1449, 1448, 1595, and 819.

Embodiment 10: Certain embodiments provide a compound comprising amodified oligonucleotide having a nucleobase sequence consisting of anyone of SEQ ID NO: 286, 817, 983, 1215, 747, 43, 355, 1602, 201, 734,1249, 208, 513, 1449, 1448, 1595, and 819.

Embodiment 11: Certain embodiments provide the compound of embodiments1-6, wherein the oligonucleotide is at least 80%, at least 85%, at least90%, at least 95% or 100% complementary to SEQ ID NO: 2 over the entirelength of the oligonucleotide.

Embodiment 12: Certain embodiments provide the compound of any one ofthe preceding embodiments, wherein the modified oligonucleotidecomprises at least one modification selected from at least one modifiedinternucleoside linkage, at least one modified nucleoside comprising amodified sugar moiety, and at least one modified nucleoside comprising amodified nucleobase.

Embodiment 13: Certain embodiments provide the compound of embodiment12, wherein the modified internucleoside linkage is a phosphorothioateinternucleoside linkage.

Embodiment 14: Certain embodiments provide the compound of embodiments12 or 13, wherein at least one nucleoside of the modifiedoligonucleotide is a 2′-substituted nucleoside or a bicyclic nucleoside.

Embodiment 15: Certain embodiments provide the compound of embodiment14, wherein the bicyclic sugar moiety of the bicyclic nucleoside isselected from the group consisting of: 4′-(CH₂)—O-2′ (LNA);4′-(CH₂)₂—O-2′ (ENA); and 4′-CH(CH₃)—O-2′ (cEt).

Embodiment 16: Certain embodiments provide the compound of any one ofembodiments 12-15, wherein the modified nucleoside is 2′-O-methoxyethylnucleoside.

Embodiment 17: Certain embodiments provide the compound of any one ofembodiments 12-16, wherein the modified nucleobase is a5-methylcytosine.

Embodiment 18: Certain embodiments provide the compound of any one ofembodiments 1-17, wherein the modified oligonucleotide has:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned immediately adjacent to andbetween the 5′ wing segment and the 3′ wing segment and wherein eachnucleoside of each wing segment comprises a modified sugar.

Embodiment 19: Certain embodiments provide the compound of any one ofclaims 1-18, wherein the modified sugar moiety of each nucleoside ofeach wing segment is selected from 2′-O-Me, 2′-MOE, and cEt sugarmoieties.

Embodiment 20: Certain embodiments provide the compound of any of oneclaims 1-19, wherein the modified oligonucleotide comprises:

-   -   a gap segment consisting of ten linked deoxynucleosides;    -   a 5′ wing segment consisting of three linked nucleosides; and    -   a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment, wherein each nucleoside of each wing segmentcomprises a cEt nucleoside; wherein each internucleoside linkage is aphosphorothioate linkage and wherein each cytosine is a5-methylcytosine.

Embodiment 21: Certain embodiments provide the compound of any of oneclaims 1-20, wherein the modified oligonucleotide comprises:

-   -   a gap segment consisting of ten linked deoxynucleosides;    -   a 5′ wing segment consisting of three linked nucleosides; and    -   a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment, wherein each nucleoside of each wing segmentcomprises a cEt nucleoside; wherein at least one internucleoside linkageis a phosphorothioate linkage and wherein each cytosine is a5-methylcytosine.

Embodiment 22: Certain embodiments provide the compound of any of thepreceding embodiments, wherein the modified oligonucleotide comprises:

-   -   a gap segment consisting of nine linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of three linked nucleosides; and    -   a 3′ wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment, wherein each nucleoside of the 5′ wing segmentcomprises a cEt nucleoside; wherein the sugar moieties of thenucleosides of the 3′ wing segment are 5′-cEt-cEt-cEt-MOE-3′; whereineach internucleoside linkage is a phosphorothioate linkage and whereineach cytosine is a 5-methylcytosine.

Embodiment 23: Certain embodiments provide the compound of any of thepreceding embodiments, wherein the modified oligonucleotide comprises:

-   -   a gap segment consisting of nine linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of three linked nucleosides; and    -   a 3′ wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment, wherein each nucleoside of the 5′ wing segmentcomprises a cEt nucleoside; wherein each sugar moiety of the nucleosidesof the 3′ wing segment are selected from cEt and 2′-MOE sugar moieties;wherein each internucleoside linkage is a phosphorothioate linkage andwherein each cytosine is a 5-methylcytosine.

Embodiment 24: Certain embodiments provide the compound of any one ofthe preceding embodiments, wherein the modified oligonucleotidecomprises:

-   -   a gap segment consisting of ten linked nucleosides;    -   a 5′ wing segment consisting of three linked nucleosides; and    -   a 3′ wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein the gap segment consists of 5′-onedeoxy, one 2′-O-methyl nucleoside, and eight deoxynucleosides-3′,wherein each nucleoside of each of the wing segments comprises a cEtnucleoside; wherein each internucleoside linkage is a phosphorothioatelinkage and wherein each cytosine is a 5-methylcytosine.

Embodiment 25: Embodiment 24: Certain embodiments provide the compoundof any one of the preceding embodiments, wherein the modifiedoligonucleotide comprises:

-   -   a gap segment consisting of ten linked nucleosides;    -   a 5′ wing segment consisting of three linked nucleosides; and    -   a 3′ wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein the nucleosides of the gap segment areselected from deoxynucleosides, cEt nucleosides and 2′-MOE nucleosides,wherein each nucleoside of each of the wing segments comprises a cEtnucleoside; wherein each internucleoside linkage is a phosphorothioatelinkage and wherein each cytosine is a 5-methylcytosine.

Embodiment 26: Certain embodiments provide the compound of any one ofembodiments 1-25, wherein the compound is single-stranded.

Embodiment 27: Certain embodiments provide the compound of any one ofembodiments 1-25, wherein the modified oligonucleotide is hybridized toa second oligonucleotide to form a double-stranded antisense compound.

Embodiment 28: Certain embodiments provide the compound of any one ofembodiments 1-27, wherein at least one of the nucleotides of themodified oligonucleotide is a ribonucleotide.

Embodiment 29: Certain embodiments provide the compound of any one ofembodiments 1-27, wherein at least one of the nucleotides of themodified oligonucleotide is a deoxyribonucleotide.

Embodiment 30: Certain embodiments provide the compound of any one ofembodiments 1-23, wherein the modified oligonucleotide consists of 10 to30 linked nucleosides.

Embodiment 31: Certain embodiments provide the compound of any one ofembodiments 1-30, wherein the modified oligonucleotide consists of 10 to30 linked nucleosides.

Embodiment 32: Certain embodiments provide the compound of any one ofembodiments 1-30, wherein the modified oligonucleotide consists of 16 to30 linked nucleosides.

Embodiment 33: Certain embodiments provide a compound comprising amodified oligonucleotide consisting of 16 linked nucleosides, whereinthe modified oligonucleotide has a nucleobase sequence selected from anyone of SEQ ID NOs: 286, 817, 983, 1215, 747, 43, 355, 1602, 201, 734,1249, 208, 513, 1449, 1448, 1595, and 819, wherein the modifiedoligonucleotide comprises:

-   -   a gap segment consisting of linked deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar.

Embodiment 34: Certain embodiments provide a compound comprising amodified oligonucleotide consisting of 16 linked nucleosides, whereinthe modified oligonucleotide has a nucleobase sequence selected from anyone of SEQ ID NOs: 286, 817, 983, 1215, 747, 43, 355, 1602, 201, 734,1249, 208, 513, 1449, 1448, and 1595, wherein the modifiedoligonucleotide comprises

-   -   a gap segment consisting of ten linked deoxynucleosides;    -   a 5′ wing segment consisting of three linked nucleosides; and    -   a 3′ wing segment consisting of three linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment; wherein the 5′ wing segment and the 3′ wing segmentcomprise cEt sugars; wherein each internucleoside linkage is aphosphorothioate linkage; and wherein each cytosine is a5-methylcytosine.

Embodiment 35: Certain embodiments provide a compound comprising amodified oligonucleotide consisting of 16 linked nucleosides, whereinthe modified oligonucleotide has a nucleobase sequence consisting of SEQID NO: 819, wherein the modified oligonucleotide comprises:

-   -   a gap segment consisting of nine linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of three linked nucleosides; and    -   a 3′ wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment, wherein each nucleoside of the 5′ wing segmentcomprises a cEt sugar; wherein the sugar residues of the nucleosides ofthe 3′ wing segment are 5′-cEt-cEt-cEt-MOE-3′; wherein eachinternucleoside linkage is a phosphorothioate linkage and wherein eachcytosine is a 5-methylcytosine.

Embodiment 36: Certain embodiments provide a a modified oligonucleotideconsisting of 16 linked nucleosides, wherein the modifiedoligonucleotide has a nucleobase sequence consisting of SEQ ID NO: 1595,wherein the modified oligonucleotide comprises:

a gap segment consisting of ten linked nucleosides;

a 5′ wing segment consisting of three linked nucleosides; and

a 3′ wing segment consisting of four linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein the gap segment consists of 5′-onedeoxy, one 2′-O-methyl nucleoside, and eight deoxynucleosides-3′,wherein each nucleoside of each of the wing segments comprises a cEtsugar; wherein each internucleoside linkage is a phosphorothioatelinkage and wherein each cytosine is a 5-methylcytosine.

Embodiment 37: Certain embodiments provide the compound of any precedingembodiment, comprising a conjugate group.

Embodiment 38: Certain embodiments provide the compound of embodiment37, wherein the conjugate group comprises a GalNAc cluster comprising1-3 GalNAc ligands.

Embodiment 39: Certain embodiments provide the compound of embodiment 37or embodiment 38, wherein the conjugate group comprises a conjugatelinker consisting of a single bond.

Embodiment 40: Certain embodiments provide the compound of any one ofembodiments 37-39, wherein the conjugate group comprises a cleavablelinker.

Embodiment 41: Certain embodiments provide the compound of any one ofembodiments 37-40, wherein the conjugate group comprises a conjugatelinker comprising 1-3 linker-nucleosides.

Embodiment 42: Certain embodiments provide the compound of any one ofembodiments 37-41, wherein the conjugate group is attached to themodified oligonucleotide at the 5′-end of the modified oligonucleotide.

Embodiment 42: Certain embodiments provide the compound of any one ofembodiments 37-41, wherein the conjugate group is attached to themodified oligonucleotide at the 3′-end of the modified oligonucleotide.

Embodiment 43: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 44: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 45: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 46: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 47: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 48: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 49: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 50: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 51: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 52: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 53: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 54: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 55: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 56: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 57: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 58: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 59: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 60: Certain embodiments provide the compound having thefollowing chemical structure or salt thereof:

Embodiment 61: Certain embodiments provide the compound of any one ofthe embodiments 43-60, wherein the compound is a sodium salt.

Embodiment 62: Certain embodiments provide the compound of any one ofthe embodiments 43-60, wherein the compound is a potassium salt.

Embodiment 63: Certain embodiments provide the chirally enrichedpopulation of the compound of any one of embodiments 1-62, wherein thepopulation is enriched for compounds having a modified oligonucleotidecomprising at least one particular phosphorothioate internucleosidelinkage having a particular stereochemical configuration.

Embodiment 64: Certain embodiments provide the chirally enrichedpopulation of embodiment 63, wherein the population is enriched forcompounds having a modified oligonucleotide comprising at least oneparticular phosphorothioate internucleoside linkage having the (Sp)configuration.

Embodiment 65: Certain embodiments provide the chirally enrichedpopulation of embodiment 63 or embodiment 64, wherein the population isenriched for compounds having a modified oligonucleotide comprising atleast one particular phosphorothioate internucleoside linkage having the(Rp) configuration.

Embodiment 66: Certain embodiments provide the chirally enrichedpopulation of claim 63, wherein the population is enriched for compoundshaving a modified oligonucleotide having a particular, independentlyselected stereochemical configuration at each phosphorothioateinternucleoside linkage.

Embodiment 67: Certain embodiments provide the chirally enrichedpopulation of embodiment 66, wherein the population is enriched foroligomeric compounds having a modified oligonucleotide having the (Sp)configuration at each phosphorothioate internucleoside linkage.

Embodiment 68: Certain embodiments provide the chirally enrichedpopulation of embodiment 66, wherein the population is enriched foroligomeric compounds having a modified oligonucleotide having the (Rp)configuration at each phosphorothioate internucleoside linkage.

Embodiment 69: Certain embodiments provide the chirally enrichedpopulation of embodiment 63 or 66, wherein wherein the population isenriched for oligomeric compounds having a modified oligonucleotidehaving at least 3 contiguous phosphorothioate internucleoside linkagesin the Sp-Sp-Rp configurations, in the 5′ to 3′ direction.

Embodiment 70: Certain embodiments provide a population of compoundshaving a modified oligonucleotide of any of embodiments 69, wherein allof the phosphorothioate internucleoside linkages of the modifiedoligonucleotide are stereorandom.

Embodiment 71: Certain embodiments provide a composition comprising thecompound of any one of embodiments 1-70 and a pharmaceuticallyacceptable carrier.

Embodiment 72: Certain embodiments provide a composition comprising acompound of any preceding embodiment, for use in therapy.

Embodiment 73: Certain embodiments provide a method of treating,preventing, or ameliorating a disease associated with HSD17B13 in anindividual comprising administering to the individual a compoundcomplementary to HSD17B13, thereby treating, preventing, or amelioratingthe disease.

Embodiment 74: Certain embodiments provide a method of administering thecompound of embodiments 1-70 or composition of embodiment 71 orembodiment 72 to an individual.

Embodiment 75: Certain embodiments provide the method of embodiments 73or 74, wherein the individual has a liver disease, NAFLD, NASH, hepaticsteatosis, hepatocellular carcinoma, alcoholic liver disease, HCVhepatitis, chronic hepatitis, hereditary hemochromatosis, or primarysclerosing cholangitis.

Embodiment 76: Certain embodiments provide the method of embodiment 73or embodiment 74, wherein the compound is an antisense compound.

Embodiment 77: Certain embodiments provide the method of any ofembodiments 73-76, wherein administering the compound ameliorates liverdamage, steatosis, liver fibrosis, liver inflammation, liver scarring orcirrhosis, liver failure, liver enlargement, elevated transaminases, orhepatic fat accumulation in the individual.

Embodiment 78: Certain embodiments provide a method of inhibitingexpression of HSD17B13 in a cell comprising contacting the cell with acompound comprising a modified oligonucleotide complementary toHSD17B13, thereby inhibiting expression of HSD17B13 in the cell.

Embodiment 79: Certain embodiments provide the method of embodiment 78,wherein the cell is in the liver of an individual.

Embodiment 80: Certain embodiments provide the method of embodiment 79,wherein the individual has, or is at risk of having, liver disease,NAFLD, NASH, hepatic steatosis, hepatocellular carcinoma, alcoholicliver disease, HCV hepatitis, chronic hepatitis, hereditaryhemochromatosis, or primary sclerosing cholangitis.

Embodiment 81: Certain embodiments provide a method of ameliorating,reducing or inhibiting liver damage, steatosis, liver fibrosis, liverinflammation, liver scarring or cirrhosis, liver failure, liverenlargement, elevated transaminases, or hepatic fat accumulation in anindividual, comprising administering a compound comprising a modifiedoligonucleotide complementary to HSD17B13 to the individual, therebyreducing or inhibiting liver damage, steatosis, liver fibrosis, liverinflammation, liver scarring or cirrhosis, liver failure, liverenlargement, elevated transaminases, or hepatic fat accumulation in theindividual.

Embodiment 82: Certain embodiments provide the method of embodiment 81,wherein the individual has, or is at risk of having, liver disease,NAFLD, NASH, hepatic steatosis, hepatocellular carcinoma, alcoholicliver disease, HCV hepatitis, chronic hepatitis, hereditaryhemochromatosis, or primary sclerosing cholangitis.

Embodiment 83: Certain embodiments provide the method of any one ofembodiments 78-82, wherein the compound is an antisense compound.

Embodiment 84: Certain embodiments provide the method of any one ofembodiments 78-83, wherein the compound is the compound of any one ofembodiments 1-70 or composition of embodiment 71 or embodiment 72.

Embodiment 85: Certain embodiments provide the method of embodiment 83or embodiment 84, wherein the compound or composition is administeredparenterally.

Embodiment 86: Certain embodiments provide the use of a compoundcomprising a modified oligonucleotide complementary to HSD17B13 fortreating, preventing, or ameliorating a disease associated withHSD17B13.

Embodiment 87: Certain embodiments provide the use of embodiment 86,wherein the disease is liver disease, NAFLD, NASH, hepatic steatosis,hepatocellular carcinoma, alcoholic liver disease, HCV hepatitis,chronic hepatitis, hereditary hemochromatosis, or primary sclerosingcholangitis.

Embodiment 88: Certain embodiments provide the use of embodiments 86 or87, wherein the compound is an antisense compound.

Embodiment 89: Certain embodiments provide the use of any one ofembodiments 86-88, wherein the compound is the compound of any one ofembodiments 1-70 or composition of embodiment 71 or embodiment 72.

Embodiment 90: Certain embodiments provide the use of a compoundcomprising a modified oligonucleotide complementary to HSD17B13 in themanufacture of a medicament for treating, preventing, or ameliorating adisease associated with HSD17B13.

Embodiment 91: Certain embodiments provide the use of embodiment 90,wherein the disease is liver disease, NAFLD, NASH, hepatic steatosis,hepatocellular carcinoma, alcoholic liver disease, HCV hepatitis,chronic hepatitis, hereditary hemochromatosis, or primary sclerosingcholangitis.

Embodiment 92: Certain embodiments provide the use of embodiments 90 or91, wherein the compound is an antisense compound.

Embodiment 93: Certain embodiments provide the use of any one ofembodiments 90-92, wherein the compound is the compound of any one ofembodiments 1-70 or composition of embodiment 71 or embodiment 72.

Certain Indications

Certain embodiments provided herein relate to methods of inhibitingHSD17B13 expression, which can be useful for treating, preventing, orameliorating a disease associated with HSD17B13 in an individual, byadministration of a compound that targets HSD17B13. In certainembodiments, the compound can be a HSD17B13 specific inhibitor. Incertain embodiments, the compound can be an antisense compound, anoligomeric compound, or an oligonucleotide targeted to HSD17B13.

Examples of diseases associated with HSD17B13 treatable, preventable,and/or ameliorable with the methods provided herein include liverdisease, NAFLD, NASH, alcoholic steatohepatitis (ASH), alcoholic liverdisease, nonalcoholic liver disease, alcoholic cirrhosis, nonalcoholiccirrhosis, steatohepatisis, hepatic steatosis, hepatocellular carcinoma,alcoholic liver disease, HCV hepatitis, chronic hepatitis, hereditaryhemochromatosis, or primary sclerosing cholangitis. Certain compoundsprovided herein are directed to compounds and compositions that reduceliver damage, steatosis, liver fibrosis, liver inflammation, liverscarring or cirrhosis, liver failure, liver enlargement, elevatedtransaminases, or hepatic fat accumulation in an animal.

In certain embodiments, a method of treating, preventing, orameliorating a disease associated with HSD17B13 in an individualcomprises administering to the individual a compound comprising aHSD17B13 specific inhibitor, thereby treating, preventing, orameliorating the disease. In certain embodiments, the individual isidentified as having, or at risk of having, a disease associated withHSD17B13. In certain embodiments, the disease is a liver disease. Incertain embodiments, the compound comprises an antisense compoundtargeted to HSD17B13. In certain embodiments, the compound comprises anoligonucleotide targeted to HSD17B13. In certain embodiments, a compoundcomprises a modified oligonucleotide consisting of 8 to 80 linkednucleosides and having a nucleobase sequence comprising at least 8contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs:8-2896. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of 16 to 80 linked nucleosides and having anucleobase sequence comprising the nucleobase sequence of any one of SEQID NOs: 8-2896. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of the nucleobase sequence of any one of SEQID NOs: 8-2896. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound. Incertain embodiments, the compound is administered to the individualparenterally. In certain embodiments, administering the compoundimproves, preserves, or prevents liver damage, steatosis, liverfibrosis, cirrhosis, elevated transaminases, or hepatic fat accumulationin an animal.

In certain embodiments, a method of treating, preventing, orameliorating liver damage, steatosis, liver fibrosis, cirrhosis,elevated transaminases, or hepatic fat accumulation in an animalcomprises administering to the individual a compound comprising aHSD17B13 specific inhibitor, thereby treating, preventing, orameliorating liver damage, steatosis, liver fibrosis, cirrhosis,elevated transaminases, or hepatic fat accumulation. In certainembodiments, the compound comprises an antisense compound targeted toHSD17B13. In certain embodiments, the compound comprises anoligonucleotide targeted to HSD17B13. In certain embodiments, a compoundcomprises consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 8-2896. In certainembodiments, a compound comprises a modified oligonucleotide consistingof 16 to 80 linked nucleosides and having a nucleobase sequencecomprising the nucleobase sequence of any one of SEQ ID NOs: 8-2896. Incertain embodiments, a compound comprises a modified oligonucleotideconsisting of the nucleobase sequence of any one of SEQ ID NOs: 8-2896.In any of the foregoing embodiments, the compound can be single-strandedor double-stranded. In any of the foregoing embodiments, the compoundcan be an antisense compound or oligomeric compound. In certainembodiments, the compound is administered to the individualparenterally. In certain embodiments, administering the compoundimproves, preserves, or prevents liver damage, steatosis, liverfibrosis, cirrhosis, elevated transaminases, or hepatic fataccumulation. In certain embodiments, the individual is identified ashaving, or at risk of having, a disease associated with HSD17B13.

In certain embodiments, a method of inhibiting expression of HSD17B13 inan individual having, or at risk of having, a disease associated withHSD17B13 comprises administering to the individual a compound comprisinga HSD17B13 specific inhibitor, thereby inhibiting expression of HSD17B13in the individual. In certain embodiments, administering the compoundinhibits expression of HSD17B13 in the liver. In certain embodiments,the disease is a liver disease. In certain embodiments, the individualhas, or is at risk of having, liver disease, NAFLD, NASH, alcoholicsteatohepatitis (ASH), alcoholic liver disease, nonalcoholic liverdisease, alcoholic cirrhosis, nonalcoholic cirrhosis, steatohepatisis,hepatic steatosis, hepatocellular carcinoma, alcoholic liver disease,HCV hepatitis, chronic hepatitis, hereditary hemochromatosis, or primarysclerosing cholangitis. In certain embodiments, the individual has, oris at risk of having, liver damage, steatosis, liver fibrosis,cirrhosis, elevated transaminases, or hepatic fat accumulation. Incertain embodiments, the compound comprises an antisense compoundtargeted to HSD17B13. In certain embodiments, the compound comprises anoligonucleotide targeted to HSD17B13. In certain embodiments, a compoundcomprises consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 8-2896. In certainembodiments, a compound comprises a modified oligonucleotide consistingof 16 to 80 linked nucleosides and having a nucleobase sequencecomprising the nucleobase sequence of any one of SEQ ID NOs: 8-2896. Incertain embodiments, a compound comprises a modified oligonucleotideconsisting of the nucleobase sequence of any one of SEQ ID NOs: 8-2896.In any of the foregoing embodiments, the compound can be single-strandedor double-stranded. In any of the foregoing embodiments, the compoundcan be an antisense compound or oligomeric compound. In certainembodiments, the compound is administered to the individualparenterally. In certain embodiments, administering the compoundimproves, preserves, or prevents liver damage, steatosis, liverfibrosis, cirrhosis, elevated transaminases, or hepatic fataccumulation.

In certain embodiments, a method of inhibiting expression of HSD17B13 ina cell comprises contacting the cell with a compound comprising aHSD17B13 specific inhibitor, thereby inhibiting expression of HSD17B13in the cell. In certain embodiments, the cell is a hepatocyte. Incertain embodiments, the cell is in the liver. In certain embodiments,the cell is in the liver of an individual who has, or is at risk ofhaving, liver damage, steatosis, liver fibrosis, cirrhosis, elevatedtransaminases, or hepatic fat accumulation. In certain embodiments, thecompound comprises an antisense compound targeted to HSD17B13. Incertain embodiments, the compound comprises an oligonucleotide targetedto HSD17B13. In certain embodiments, a compound comprises consisting of8 to 80 linked nucleosides and having a nucleobase sequence comprisingat least 8 contiguous nucleobases of any of the nucleobase sequences ofSEQ ID NOs: 8-2896. In certain embodiments, a compound comprises amodified oligonucleotide consisting of 16 to 80 linked nucleosides andhaving a nucleobase sequence comprising the nucleobase sequence of anyone of SEQ ID NOs: 8-2896. In certain embodiments, a compound comprisesa modified oligonucleotide consisting of the nucleobase sequence of anyone of SEQ ID NOs: 8-2896. In any of the foregoing embodiments, thecompound can be single-stranded or double-stranded. In any of theforegoing embodiments, the compound can be an antisense compound oroligomeric compound.

In certain embodiments, a method of reducing or inhibiting liver damage,steatosis, liver fibrosis, cirrhosis, elevated transaminases, or hepaticfat accumulation in an individual having, or at risk of having, adisease associated with HSD17B13 comprises administering to theindividual a compound comprising a HSD17B13 specific inhibitor, therebyreducing or inhibiting liver damage, steatosis, liver fibrosis,cirrhosis, elevated transaminases, or hepatic fat accumulation in theindividual. In certain embodiments, the individual has, or is at risk ofhaving, liver disease, NAFLD, NASH, alcoholic steatohepatitis (ASH),alcoholic liver disease, nonalcoholic liver disease, alcoholiccirrhosis, nonalcoholic cirrhosis, steatohepatisis, hepatic steatosis,hepatocellular carcinoma, alcoholic liver disease, HCV hepatitis,chronic hepatitis, hereditary hemochromatosis, or primary sclerosingcholangitis. In certain embodiments, the compound comprises an antisensecompound targeted to HSD17B13. In certain embodiments, the compoundcomprises an oligonucleotide targeted to HSD17B13. In certainembodiments, a compound comprises consisting of 8 to 80 linkednucleosides and having a nucleobase sequence comprising at least 8contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs:8-2896. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of 16 to 80 linked nucleosides and having anucleobase sequence comprising the nucleobase sequence of any one of SEQID NOs: 8-2896. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of the nucleobase sequence of any one of SEQID NOs: 8-2896. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound. Incertain embodiments, the compound is administered to the individualparenterally. In certain embodiments, the individual is identified ashaving, or at risk of having, a disease associated with HSD17B13.

Certain embodiments are drawn to a compound comprising a HSD17B13specific inhibitor for use in treating a disease associated withHSD17B13. In certain embodiments, the disease is liver disease, NAFLD,NASH, alcoholic steatohepatitis (ASH), alcoholic liver disease,nonalcoholic liver disease, alcoholic cirrhosis, nonalcoholic cirrhosis,steatohepatisis, hepatic steatosis, hepatocellular carcinoma, alcoholicliver disease, HCV hepatitis, chronic hepatitis, hereditaryhemochromatosis, or primary sclerosing cholangitis. In certainembodiments, the compound comprises an antisense compound targeted toHSD17B13. In certain embodiments, the compound comprises anoligonucleotide targeted to HSD17B13. In certain embodiments, a compoundcomprises consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 8-2896. In certainembodiments, a compound comprises a modified oligonucleotide consistingof 16 to 80 linked nucleosides and having a nucleobase sequencecomprising the nucleobase sequence of any one of SEQ ID NOs: 8-2896. Incertain embodiments, a compound comprises a modified oligonucleotideconsisting of the nucleobase sequence of any one of SEQ ID NOs: 8-2896.In any of the foregoing embodiments, the compound can be single-strandedor double-stranded. In any of the foregoing embodiments, the compoundcan be an antisense compound or oligomeric compound. In certainembodiments, the compound is administered to the individualparenterally.

Certain embodiments are drawn to a compound comprising a HSD17B13specific inhibitor for use in reducing or inhibiting liver damage,steatosis, liver fibrosis, cirrhosis, elevated transaminases, or hepaticfat accumulation in an individual having, or at risk of having, liverdisease, NAFLD, NASH, alcoholic steatohepatitis (ASH), alcoholic liverdisease, nonalcoholic liver disease, alcoholic cirrhosis, nonalcoholiccirrhosis, steatohepatisis, hepatic steatosis, hepatocellular carcinoma,alcoholic liver disease, HCV hepatitis, chronic hepatitis, hereditaryhemochromatosis, or primary sclerosing cholangitis. In certainembodiments, the compound comprises an antisense compound targeted toHSD17B13. In certain embodiments, the compound comprises anoligonucleotide targeted to HSD17B13. In certain embodiments, a compoundcomprises consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 8-2896. In certainembodiments, a compound comprises a modified oligonucleotide consistingof 16 to 80 linked nucleosides and having a nucleobase sequencecomprising the nucleobase sequence of any one of SEQ ID NOs: 8-2896. Incertain embodiments, a compound comprises a modified oligonucleotideconsisting of the nucleobase sequence of any one of SEQ ID NOs: 8-2896.In any of the foregoing embodiments, the compound can be single-strandedor double-stranded. In any of the foregoing embodiments, the compoundcan be an antisense compound or oligomeric compound.

Certain embodiments are drawn to the use of a compound comprising aHSD17B13 specific inhibitor for the manufacture or preparation of amedicament for treating a disease associated with HSD17B13. Certainembodiments are drawn to the use of a compound comprising a HSD17B13specific inhibitor for the preparation of a medicament for treating adisease associated with HSD17B13. In certain embodiments, the disease isa liver disease. In certain embodiments, the disease is liver disease,NAFLD, NASH, alcoholic steatohepatitis (ASH), alcoholic liver disease,nonalcoholic liver disease, alcoholic cirrhosis, nonalcoholic cirrhosis,steatohepatisis, hepatic steatosis, hepatocellular carcinoma, alcoholicliver disease, HCV hepatitis, chronic hepatitis, hereditaryhemochromatosis, or primary sclerosing cholangitis. In certainembodiments, the compound comprises an antisense compound targeted toHSD17B13. In certain embodiments, the compound comprises anoligonucleotide targeted to HSD17B13. In certain embodiments, a compoundcomprises consisting of 8 to 80 linked nucleosides and having anucleobase sequence comprising at least 8 contiguous nucleobases of anyof the nucleobase sequences of SEQ ID NOs: 8-2896. In certainembodiments, a compound comprises a modified oligonucleotide consistingof 16 to 80 linked nucleosides and having a nucleobase sequencecomprising the nucleobase sequence of any one of SEQ ID NOs: 8-2896. Incertain embodiments, a compound comprises a modified oligonucleotideconsisting of the nucleobase sequence of any one of SEQ ID NOs: 8-2896.In any of the foregoing embodiments, the compound can be single-strandedor double-stranded. In any of the foregoing embodiments, the compoundcan be an antisense compound or oligomeric compound.

Certain embodiments are drawn to the use of a compound comprising aHSD17B13 specific inhibitor for the manufacture or preparation of amedicament for reducing or inhibiting liver damage, steatosis, liverfibrosis, cirrhosis, elevated transaminases, or hepatic fat accumulationin an individual having, or at risk of having, a disease associated withHSD17B13. In certain embodiments, the disease is liver disease, NAFLD,NASH, alcoholic steatohepatitis (ASH), alcoholic liver disease,nonalcoholic liver disease, alcoholic cirrhosis, nonalcoholic cirrhosis,steatohepatisis, hepatic steatosis, hepatocellular carcinoma, alcoholicliver disease, HCV hepatitis, chronic hepatitis, hereditaryhemochromatosis, or primary sclerosing cholangitis. Certain embodimentsare drawn to use of a compound comprising a HSD17B13 specific inhibitorfor the preparation of a medicament for treating a disease associatedwith HSD17B13. In certain embodiments, the disease is liver disease,NAFLD, NASH, alcoholic liver disease, nonalcoholic liver disease,alcoholic cirrhosis, nonalcoholic cirrhosis, steatohepatisis, hepaticsteatosis, hepatocellular carcinoma, alcoholic liver disease, HCVhepatitis, chronic hepatitis, hereditary hemochromatosis, or primarysclerosing cholangitis. In certain embodiments, the compound comprisesan antisense compound targeted to HSD17B13. In certain embodiments, thecompound comprises an oligonucleotide targeted to HSD17B13. In certainembodiments, a compound comprises consisting of 8 to 80 linkednucleosides and having a nucleobase sequence comprising at least 8contiguous nucleobases of any of the nucleobase sequences of SEQ ID NOs:8-2896. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of 16 to 80 linked nucleosides and having anucleobase sequence comprising the nucleobase sequence of any one of SEQID NOs: 8-2896. In certain embodiments, a compound comprises a modifiedoligonucleotide consisting of the nucleobase sequence of any one of SEQID NOs: 8-2896. In any of the foregoing embodiments, the compound can besingle-stranded or double-stranded. In any of the foregoing embodiments,the compound can be an antisense compound or oligomeric compound.

In any of the foregoing methods or uses, the compound can be targeted toHSD17B13. In certain embodiments, the compound comprises or consists ofa modified oligonucleotide, for example, a modified oligonucleotideconsisting of 8 to 80 linked nucleosides, 10 to 30 linked nucleosides,12 to 30 linked nucleosides, or 20 linked nucleosides. In certainembodiments, the modified oligonucleotide is at least 80%, at least 85%,at least 90%, at least 95% or 100% complementary to any of thenucleobase sequences recited in SEQ ID NOs: 1-4. In certain embodiments,the modified oligonucleotide comprises at least one modifiedinternucleoside linkage, at least one modified sugar and/or at least onemodified nucleobase. In certain embodiments, the modifiedinternucleoside linkage is a phosphorothioate internucleoside linkage,the modified sugar is a bicyclic sugar or a 2′-O-methoxyethyl modifiedsugar, and the modified nucleobase is a 5-methylcytosine. In certainembodiments, the modified oligonucleotide comprises a gap segmentconsisting of linked deoxynucleosides; a 5′ wing segment consisting oflinked nucleosides; and a 3′ wing segment consisting of linkednucleosides, wherein the gap segment is positioned immediately adjacentto and between the 5′ wing segment and the 3′ wing segment and whereineach nucleoside of each wing segment comprises a modified sugar.

In any of the foregoing embodiments, the modified oligonucleotideconsists of 12 to 30, 15 to 30, 15 to 25, 15 to 24, 16 to 24, 17 to 24,18 to 24, 19 to 24, 20 to 24, 19 to 22, 20 to 22, 16 to 20, or 16 or 20linked nucleosides. In certain embodiments, the modified oligonucleotideis at least 80%, at least 85%, at least 90%, at least 95% or 100%complementary to any of the nucleobase sequences recited in SEQ ID NOs:1-4.

In any of the foregoing methods or uses, the compound comprises orconsists of a modified oligonucleotide consisting of 16 to 30 linkednucleosides and having a nucleobase sequence comprising any one of SEQID NOs: 8-2896, wherein the modified oligonucleotide has:

-   -   a gap segment consisting of linked 2′-deoxynucleosides;    -   a 5′ wing segment consisting of linked nucleosides; and    -   a 3′ wing segment consisting of linked nucleosides;

wherein the gap segment is positioned between the 5′ wing segment andthe 3′ wing segment and wherein each nucleoside of each wing segmentcomprises a modified sugar. In certain embodiments, the modifiedoligonucleotide is 16-30 linked nucleosides in length. In certainembodiments, the modified oligonucleotide is 16 linked nucleosides inlength.

In any of the foregoing methods or uses, the compound can beadministered parenterally. For example, in certain embodiments thecompound can be administered through injection or infusion. Parenteraladministration includes subcutaneous administration, intravenousadministration, intramuscular administration, intraarterialadministration, intraperitoneal administration, or intracranialadministration, e.g. intrathecal or intracerebroventricularadministration.

Certain Compounds

In certain embodiments, compounds described herein can be antisensecompounds. In certain embodiments, the antisense compound comprises orconsists of an oligomeric compound. In certain embodiments, theoligomeric compound comprises a modified oligonucleotide. In certainembodiments, the modified oligonucleotide has a nucleobase sequencecomplementary to that of a target nucleic acid.

In certain embodiments, a compound described herein comprises orconsists of a modified oligonucleotide. In certain embodiments, themodified oligonucleotide has a nucleobase sequence complementary to thatof a target nucleic acid.

In certain embodiments, a compound or antisense compound issingle-stranded. Such a single-stranded compound or antisense compoundcomprises or consists of an oligomeric compound. In certain embodiments,such an oligomeric compound comprises or consists of an oligonucleotideand optionally a conjugate group. In certain embodiments, theoligonucleotide is an antisense oligonucleotide. In certain embodiments,the oligonucleotide is modified. In certain embodiments, theoligonucleotide of a single-stranded antisense compound or oligomericcompound comprises a self-complementary nucleobase sequence.

In certain embodiments, compounds are double-stranded. Suchdouble-stranded compounds comprise a first modified oligonucleotidehaving a region complementary to a target nucleic acid and a secondmodified oligonucleotide having a region complementary to the firstmodified oligonucleotide. In certain embodiments, the modifiedoligonucleotide is an RNA oligonucleotide. In such embodiments, thethymine nucleobase in the modified oligonucleotide is replaced by auracil nucleobase. In certain embodiments, compound comprises aconjugate group. In certain embodiments, one of the modifiedoligonucleotides is conjugated. In certain embodiments, both themodified oligonucleotides are conjugated. In certain embodiments, thefirst modified oligonucleotide is conjugated. In certain embodiments,the second modified oligonucleotide is conjugated. In certainembodiments, the first modified oligonucleotide is 16-30 linkednucleosides in length and the second modified oligonucleotide is 16-30linked nucleosides in length. In certain embodiments, one of themodified oligonucleotides has a nucleobase sequence comprising at least8 contiguous nucleobases of any of SEQ ID NOs: 8-2035.

In certain embodiments, antisense compounds are double-stranded. Suchdouble-stranded antisense compounds comprise a first oligomeric compoundhaving a region complementary to a target nucleic acid and a secondoligomeric compound having a region complementary to the firstoligomeric compound. The first oligomeric compound of such doublestranded antisense compounds typically comprises or consists of amodified oligonucleotide and optionally a conjugate group. Theoligonucleotide of the second oligomeric compound of such adouble-stranded antisense compound may be modified or unmodified. Eitheror both oligomeric compounds of a double-stranded antisense compound maycomprise a conjugate group. The oligomeric compounds of double-strandedantisense compounds may include non-complementary overhangingnucleosides.

Examples of single-stranded and double-stranded compounds include, butare not limited to, oligonucleotides, siRNAs, microRNA targetingoligonucleotides, and single-stranded RNAi compounds, such as smallhairpin RNAs (shRNAs), single-stranded siRNAs (ssRNAs), and microRNAmimics.

In certain embodiments, a compound described herein has a nucleobasesequence that, when written in the 5′ to 3′ direction, comprises thereverse complement of the target segment of a target nucleic acid towhich it is targeted.

In certain embodiments, a compound described herein comprises anoligonucleotide 12 to 30 linked subunits in length. In certainembodiments, a compound described herein comprises an oligonucleotide 12to 22 linked subunits in length. In certain embodiments, compounddescribed herein comprises an oligonucleotide 14 to 30 linked subunitsin length. In certain embodiments, compound described herein comprisesan oligonucleotide 14 to 20 linked subunits in length. In certainembodiments, a compound described herein comprises an oligonucleotide 15to 30 linked subunits in length. In certain embodiments, a compounddescribed herein comprises an oligonucleotide 15 to 20 linked subunitsin length. In certain embodiments, a compound described herein comprisesan oligonucleotide 16 to 30 linked subunits in length. In certainembodiments, a compound described herein comprises an oligonucleotide 16to 20 linked subunits in length. In certain embodiments, a compounddescribed herein comprises an oligonucleotide 17 to 30 linked subunitsin length. In certain embodiments, a compound described herein comprisesan oligonucleotide 17 to 20 linked subunits in length. In certainembodiments, a compound described herein comprises an oligonucleotide 18to 30 linked subunits in length. In certain embodiments, a compounddescribed herein comprises an oligonucleotide 18 to 20 linked subunitsin length. In certain embodiments, a compound described herein comprisesan oligonucleotide 20 to 30 linked subunits in length. In other words,such oligonucleotides are 12 to 30 linked subunits, 14 to 30 linkedsubunits, 14 to 20 subunits, 15 to 30 subunits, 15 to 20 subunits, 16 to30 subunits, 16 to 20 subunits, 17 to 30 subunits, 17 to 20 subunits, 18to 30 subunits, 18 to 20 subunits, or 20 to 30 subunits in length,respectively. In certain embodiments, a compound described hereincomprises an oligonucleotide 14 linked subunits in length. In certainembodiments, a compound described herein comprises an oligonucleotide 16linked subunits in length. In certain embodiments, a compound describedherein comprises an oligonucleotide 17 linked subunits in length. Incertain embodiments, compound described herein comprises anoligonucleotide 18 linked subunits in length. In certain embodiments, acompound described herein comprises an oligonucleotide 19 linkedsubunits in length. In certain embodiments, a compound described hereincomprises an oligonucleotide 20 linked subunits in length. In otherembodiments, a compound described herein comprises an oligonucleotide 8to 80, 12 to 50, 13 to 30, 13 to 50, 14 to 30, 14 to 50, 15 to 30, 15 to50, 16 to 30, 16 to 50, 17 to 30, 17 to 50, 18 to 22, 18 to 24, 18 to30, 18 to 50, 19 to 22, 19 to 30, 19 to 50, or 20 to 30 linked subunits.In certain such embodiments, the compound described herein comprises anoligonucleotide 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, or 30 linked subunits in length, or arange defined by any two of the above values. In some embodiments thelinked subunits are nucleotides, nucleosides, or nucleobases.

In certain embodiments, the compound may further comprise additionalfeatures or elements, such as a conjugate group, that are attached tothe oligonucleotide. In certain embodiments, such compounds areantisense compounds. In certain embodiments, such compounds areoligomeric compounds. In embodiments where a conjugate group comprises anucleoside (i.e. a nucleoside that links the conjugate group to theoligonucleotide), the nucleoside of the conjugate group is not countedin the length of the oligonucleotide.

In certain embodiments, compounds may be shortened or truncated. Forexample, a single subunit may be deleted from the 5′ end (5′truncation), or alternatively from the 3′ end (3′ truncation). Ashortened or truncated compound targeted to a HSD17B13 nucleic acid mayhave two subunits deleted from the 5′ end, or alternatively, may havetwo subunits deleted from the 3′ end of the compound. Alternatively, thedeleted nucleosides may be dispersed throughout the compound.

When a single additional subunit is present in a lengthened compound,the additional subunit may be located at the 5′ or 3′ end of thecompound. When two or more additional subunits are present, the addedsubunits may be adjacent to each other, for example, in a compoundhaving two subunits added to the 5′ end (5′ addition), or alternatively,to the 3′ end (3′ addition) of the compound. Alternatively, the addedsubunits may be dispersed throughout the compound.

It is possible to increase or decrease the length of a compound, such asan oligonucleotide, and/or introduce mismatch bases without eliminatingactivity (Woolf et al. Proc. Natl. Acad. Sci. USA 1992, 89:7305-7309;Gautschi et al. J. Natl. Cancer Inst. March 2001, 93:463-471; Maher andDolnick Nuc. Acid. Res. 1998, 16:3341-3358). However, seemingly smallchanges in oligonucleotide sequence, chemistry and motif can make largedifferences in one or more of the many properties required for clinicaldevelopment (Seth et al. J. Med. Chem. 2009, 52, 10; Egli et al. J. Am.Chem. Soc. 2011, 133, 16642).

In certain embodiments, compounds described herein are interfering RNAcompounds (RNAi), which include double-stranded RNA compounds (alsoreferred to as short-interfering RNA or siRNA) and single-stranded RNAicompounds (or ssRNA). Such compounds work at least in part through theRISC pathway to degrade and/or sequester a target nucleic acid (thus,include microRNA/microRNA-mimic compounds). As used herein, the termsiRNA is meant to be equivalent to other terms used to describe nucleicacid molecules that are capable of mediating sequence-specific RNAi, forexample, short interfering RNA (siRNA), double-stranded RNA (dsRNA),micro-RNA (miRNA), short hairpin RNA (shRNA), short interferingoligonucleotide, short interfering nucleic acid, short interferingmodified oligonucleotide, chemically modified siRNA,post-transcriptional gene silencing RNA (ptgsRNA), and others. Inaddition, as used herein, the term “RNAi” is meant to be equivalent toother terms used to describe sequence-specific RNA interference, such aspost transcriptional gene silencing, translational inhibition, orepigenetics.

In certain embodiments, a compound described herein can comprise any ofthe oligonucleotide sequences targeted to HSD17B13 described herein. Incertain embodiments, the compound can be double-stranded. In certainembodiments, the compound comprises a first strand comprising at leastan 8, 9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion ofany one of SEQ ID NOs: 8-2035 and a second strand. In certainembodiments, the compound comprises a first strand comprising thenucleobase sequence of any one of SEQ ID NOs: 8-2035 and a secondstrand. In certain embodiments, the compound comprises ribonucleotidesin which the first strand has uracil (U) in place of thymine (T) in anyone of SEQ ID NOs: 8-2035. In certain embodiments, the compoundcomprises (i) a first strand comprising a nucleobase sequencecomplementary to the site on HSD17B13 to which any of SEQ ID NOs: 8-2035is targeted, and (ii) a second strand. In certain embodiments, thecompound comprises one or more modified nucleotides in which the 2′position of the sugar contains a halogen (such as fluorine group; 2′-F)or contains an alkoxy group (such as a methoxy group; 2′-OMe). Incertain embodiments, the compound comprises at least one 2′-F sugarmodification and at least one 2′-OMe sugar modification. In certainembodiments, the at least one 2′-F sugar modification and at least one2′-OMe sugar modification are arranged in an alternating pattern for atleast 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or20 contiguous nucleobases along a strand of the dsRNA compound. Incertain embodiments, the compound comprises one or more linkages betweenadjacent nucleotides other than a naturally-occurring phosphodiesterlinkage. Examples of such linkages include phosphoramide,phosphorothioate, and phosphorodithioate linkages. The compounds mayalso be chemically modified nucleic acid molecules as taught in U.S.Pat. No. 6,673,661. In other embodiments, the compound contains one ortwo capped strands, as disclosed, for example, by WO 00/63364, filedApr. 19, 2000.

In certain embodiments, the first strand of the compound is an siRNAguide strand and the second strand of the compound is an siRNA passengerstrand. In certain embodiments, the second strand of the compound iscomplementary to the first strand. In certain embodiments, each strandof the compound is 16, 17, 18, 19, 20, 21, 22, or 23 linked nucleosidesin length. In certain embodiments, the first or second strand of thecompound can comprise a conjugate group.

In certain embodiments, a compound described herein can comprise any ofthe oligonucleotide sequences targeted to HSD17B13 described herein. Incertain embodiments, the compound is single stranded. In certainembodiments, such a compound is a single-stranded RNAi (ssRNAi)compound. In certain embodiments, the compound comprises at least an 8,9, 10, 11, 12, 13, 14, 15, or 16 contiguous nucleobase portion of anyone of SEQ ID NOs: 8-2035. In certain embodiments, the compoundcomprises the nucleobase sequence of any one of SEQ ID NOs: 8-2035. Incertain embodiments, the compound comprises ribonucleotides in whichuracil (U) is in place of thymine (T) in any one of SEQ ID NOs: 8-2035.In certain embodiments, the compound comprises a nucleobase sequencecomplementary to the site on HSD17B13 to which any of SEQ ID NOs: 8-2035is targeted. In certain embodiments, the compound comprises one or moremodified nucleotides in which the 2′ position in the sugar contains ahalogen (such as fluorine group; 2′-F) or contains an alkoxy group (suchas a methoxy group; 2′-OMe). In certain embodiments, the compoundcomprises at least one 2′-F sugar modification and at least one 2′-OMesugar modification. In certain embodiments, the at least one 2′-F sugarmodification and at least one 2′-OMe sugar modification are arranged inan alternating pattern for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases along a strandof the compound. In certain embodiments, the compound comprises one ormore linkages between adjacent nucleotides other than anaturally-occurring phosphodiester linkage. Examples of such linkagesinclude phosphoramide, phosphorothioate, and phosphorodithioatelinkages. The compounds may also be chemically modified nucleic acidmolecules as taught in U.S. Pat. No. 6,673,661. In other embodiments,the compound contains a capped strand, as disclosed, for example, by WO00/63364, filed Apr. 19, 2000. In certain embodiments, the compoundconsists of 16, 17, 18, 19, 20, 21, 22, or 23 linked nucleosides. Incertain embodiments, the compound can comprise a conjugate group.

Certain Mechanisms

In certain embodiments, compounds described herein comprise or consistof modified oligonucleotides. In certain embodiments, compoundsdescribed herein are antisense compounds. In certain embodiments,compounds comprise oligomeric compounds. In certain embodiments,compounds described herein are capable of hybridizing to a targetnucleic acid, resulting in at least one antisense activity. In certainembodiments, compounds described herein selectively affect one or moretarget nucleic acid. Such compounds comprise a nucleobase sequence thathybridizes to one or more target nucleic acid, resulting in one or moredesired antisense activity and does not hybridize to one or morenon-target nucleic acid or does not hybridize to one or more non-targetnucleic acid in such a way that results in a significant undesiredantisense activity.

In certain antisense activities, hybridization of a compound describedherein to a target nucleic acid results in recruitment of a protein thatcleaves the target nucleic acid. For example, certain compoundsdescribed herein result in RNase H mediated cleavage of the targetnucleic acid. RNase H is a cellular endonuclease that cleaves the RNAstrand of an RNA:DNA duplex. The DNA in such an RNA:DNA duplex need notbe unmodified DNA. In certain embodiments, compounds described hereinare sufficiently “DNA-like” to elicit RNase H activity. Further, incertain embodiments, one or more non-DNA-like nucleoside in the gap of agapmer is tolerated.

In certain antisense activities, compounds described herein or a portionof the compound is loaded into an RNA-induced silencing complex (RISC),ultimately resulting in cleavage of the target nucleic acid. Forexample, certain compounds described herein result in cleavage of thetarget nucleic acid by Argonaute. Compounds that are loaded into RISCare RNAi compounds. RNAi compounds may be double-stranded (siRNA) orsingle-stranded (ssRNA).

In certain embodiments, hybridization of compounds described herein to atarget nucleic acid does not result in recruitment of a protein thatcleaves that target nucleic acid. In certain such embodiments,hybridization of the compound to the target nucleic acid results inalteration of splicing of the target nucleic acid. In certainembodiments, hybridization of the compound to a target nucleic acidresults in inhibition of a binding interaction between the targetnucleic acid and a protein or other nucleic acid. In certain suchembodiments, hybridization of the compound to a target nucleic acidresults in alteration of translation of the target nucleic acid.

Antisense activities may be observed directly or indirectly. In certainembodiments, observation or detection of an antisense activity involvesobservation or detection of a change in an amount of a target nucleicacid or protein encoded by such target nucleic acid, a change in theratio of splice variants of a nucleic acid or protein, and/or aphenotypic change in a cell or animal.

Target Nucleic Acids, Target Regions and Nucleotide Sequences

In certain embodiments, compounds described herein comprise or consistof an oligonucleotide comprising a region that is complementary to atarget nucleic acid. In certain embodiments, the target nucleic acid isan endogenous RNA molecule. In certain embodiments, the target nucleicacid encodes a protein. In certain such embodiments, the target nucleicacid is selected from an mRNA and a pre-mRNA, including intronic, exonicand untranslated regions. In certain embodiments, the target RNA is anmRNA. In certain embodiments, the target nucleic acid is a pre-mRNA. Incertain such embodiments, the target region is entirely within anintron. In certain embodiments, the target region spans an intron/exonjunction. In certain embodiments, the target region is at least 50%within an intron.

Nucleotide sequences that encode HSD17B13 include, without limitation,the following: RefSeq or GENBANK Accession No. NM_178135.4 (incorporatedby reference, disclosed herein as SEQ ID NO: 1), the complement ofGENBANK Accession No. NC_000004.12 truncated from nucleotides 87301001to U.S. Pat. No. 87,326,000 (incorporated by reference, disclosed hereinas SEQ ID NO: 2), the sequence listed as SEQ ID NO: 3, or GENBANKAccession No. NM_001136230.2 (incorporated by reference, disclosedherein as SEQ ID NO: 4).

Hybridization

In some embodiments, hybridization occurs between a compound disclosedherein and a HSD17B13 nucleic acid. The most common mechanism ofhybridization involves hydrogen bonding (e.g., Watson-Crick, Hoogsteenor reversed Hoogsteen hydrogen bonding) between complementarynucleobases of the nucleic acid molecules.

Hybridization can occur under varying conditions. Hybridizationconditions are sequence-dependent and are determined by the nature andcomposition of the nucleic acid molecules to be hybridized.

Methods of determining whether a sequence is specifically hybridizableto a target nucleic acid are well known in the art. In certainembodiments, the compounds provided herein are specifically hybridizablewith a HSD17B13 nucleic acid.

Complementarity

An oligonucleotide is said to be complementary to another nucleic acidwhen the nucleobase sequence of such oligonucleotide or one or moreregions thereof matches the nucleobase sequence of anotheroligonucleotide or nucleic acid or one or more regions thereof when thetwo nucleobase sequences are aligned in opposing directions. Nucleobasematches or complementary nucleobases, as described herein, are limitedto the following pairs: adenine (A) and thymine (T), adenine (A) anduracil (U), cytosine (C) and guanine (G), and 5-methyl cytosine (mC) andguanine (G), unless otherwise specified. Complementary oligonucleotidesand/or nucleic acids need not have nucleobase complementarity at eachnucleoside and may include one or more nucleobase mismatches. Anoligonucleotide is fully complementary or 100% complementary when sucholigonucleotides have nucleobase matches at each nucleoside without anynucleobase mismatches.

In certain embodiments, compounds described herein comprise or consistof modified oligonucleotides. In certain embodiments, compoundsdescribed herein are antisense compounds. In certain embodiments,compounds comprise oligomeric compounds. Non-complementary nucleobasesbetween a compound and a HSD17B13 nucleic acid may be tolerated providedthat the compound remains able to specifically hybridize to a targetnucleic acid. Moreover, a compound may hybridize over one or moresegments of a HSD17B13 nucleic acid such that intervening or adjacentsegments are not involved in the hybridization event (e.g., a loopstructure, mismatch or hairpin structure).

In certain embodiments, the compounds provided herein, or a specifiedportion thereof are at least, or are up to 70%, 80%, 85%, 86%, 87%, 88%,89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%complementary to a HSD17B13 nucleic acid, a target region, targetsegment, or specified portion thereof. In certain embodiments, thecompounds provided herein, or a specified portion thereof, are 70% to75%, 75% to 80%, 80% to 85%, 85% to 90%, 90% to 95%, 95% to 100%, or anynumber in between these ranges, complementary to a HSD17B13 nucleicacid, a target region, target segment, or specified portion thereof.Percent complementarity of a compound with a target nucleic acid can bedetermined using routine methods.

For example, a compound in which 18 of 20 nucleobases of the compoundare complementary to a target region, and would therefore specificallyhybridize, would represent 90 percent complementarity. In this example,the remaining non-complementary nucleobases may be clustered orinterspersed with complementary nucleobases and need not be contiguousto each other or to complementary nucleobases. As such, a compound whichis 18 nucleobases in length having four non-complementary nucleobaseswhich are flanked by two regions of complete complementarity with thetarget nucleic acid would have 77.8% overall complementarity with thetarget nucleic acid. Percent complementarity of a compound with a regionof a target nucleic acid can be determined routinely using BLASTprograms (basic local alignment search tools) and PowerBLAST programsknown in the art (Altschul et al., J. Mol. Biol., 1990, 215, 403 410;Zhang and Madden, Genome Res., 1997, 7, 649 656). Percent homology,sequence identity or complementarity, can be determined by, for example,the Gap program (Wisconsin Sequence Analysis Package, Version 8 forUnix, Genetics Computer Group, University Research Park, Madison Wis.),using default settings, which uses the algorithm of Smith and Waterman(Adv. Appl. Math., 1981, 2, 482 489).

In certain embodiments, compounds described herein, or specifiedportions thereof, are fully complementary (i.e. 100% complementary) to atarget nucleic acid, or specified portion thereof. For example, acompound may be fully complementary to a HSD17B13 nucleic acid, or atarget region, or a target segment or target sequence thereof. As usedherein, “fully complementary” means each nucleobase of a compound iscomplementary to the corresponding nucleobase of a target nucleic acid.For example, a 20 nucleobase compound is fully complementary to a targetsequence that is 400 nucleobases long, so long as there is acorresponding 20 nucleobase portion of the target nucleic acid that isfully complementary to the compound. “Fully complementary” can also beused in reference to a specified portion of the first and/or the secondnucleic acid. For example, a 20 nucleobase portion of a 30 nucleobasecompound can be “fully complementary” to a target sequence that is 400nucleobases long. The 20 nucleobase portion of the 30 nucleobasecompound is fully complementary to the target sequence if the targetsequence has a corresponding 20 nucleobase portion wherein eachnucleobase is complementary to the 20 nucleobase portion of thecompound. At the same time, the entire 30 nucleobase compound may or maynot be fully complementary to the target sequence, depending on whetherthe remaining 10 nucleobases of the compound are also complementary tothe target sequence.

In certain embodiments, compounds described herein comprise one or moremismatched nucleobases relative to the target nucleic acid. In certainsuch embodiments, antisense activity against the target is reduced bysuch mismatch, but activity against a non-target is reduced by a greateramount. Thus, in certain such embodiments, selectivity of the compoundis improved. In certain embodiments, the mismatch is specificallypositioned within an oligonucleotide having a gapmer motif. In certainsuch embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, or 8from the 5′-end of the gap region. In certain such embodiments, themismatch is at position 9, 8, 7, 6, 5, 4, 3, 2, 1 from the 3′-end of thegap region. In certain such embodiments, the mismatch is at position 1,2, 3, or 4 from the 5′-end of the wing region. In certain suchembodiments, the mismatch is at position 4, 3, 2, or 1 from the 3′-endof the wing region. In certain embodiments, the mismatch is specificallypositioned within an oligonucleotide not having a gapmer motif. Incertain such embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, or 12 from the 5′-end of the oligonucleotide. Incertain such embodiments, the mismatch is at position, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or 12 from the 3′-end of the oligonucleotide.

The location of a non-complementary nucleobase may be at the 5′ end or3′ end of the compound. Alternatively, the non-complementary nucleobaseor nucleobases may be at an internal position of the compound. When twoor more non-complementary nucleobases are present, they may becontiguous (i.e. linked) or non-contiguous. In one embodiment, anon-complementary nucleobase is located in the wing segment of a gapmeroligonucleotide.

In certain embodiments, compounds described herein that are, or are upto 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleobases in lengthcomprise no more than 4, no more than 3, no more than 2, or no more than1 non-complementary nucleobase(s) relative to a target nucleic acid,such as a HSD17B13 nucleic acid, or specified portion thereof.

In certain embodiments, compounds described herein that are, or are upto 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, or 30 nucleobases in length comprise no more than 6, no morethan 5, no more than 4, no more than 3, no more than 2, or no more than1 non-complementary nucleobase(s) relative to a target nucleic acid,such as a HSD17B13 nucleic acid, or specified portion thereof.

In certain embodiments, compounds described herein also include thosewhich are complementary to a portion of a target nucleic acid. As usedherein, “portion” refers to a defined number of contiguous (i.e. linked)nucleobases within a region or segment of a target nucleic acid. A“portion” can also refer to a defined number of contiguous nucleobasesof a compound. In certain embodiments, the compounds, are complementaryto at least an 8 nucleobase portion of a target segment. In certainembodiments, the compounds are complementary to at least a 9 nucleobaseportion of a target segment. In certain embodiments, the compounds arecomplementary to at least a 10 nucleobase portion of a target segment.In certain embodiments, the compounds are complementary to at least an11 nucleobase portion of a target segment. In certain embodiments, thecompounds are complementary to at least a 12 nucleobase portion of atarget segment. In certain embodiments, the compounds are complementaryto at least a 13 nucleobase portion of a target segment. In certainembodiments, the compounds are complementary to at least a 14 nucleobaseportion of a target segment. In certain embodiments, the compounds arecomplementary to at least a 15 nucleobase portion of a target segment.In certain embodiments, the compounds are complementary to at least a 16nucleobase portion of a target segment. Also contemplated are compoundsthat are complementary to at least a 9, 10, 17, 18, 19, 20, or morenucleobase portion of a target segment, or a range defined by any two ofthese values.

Identity

The compounds provided herein may also have a defined percent identityto a particular nucleotide sequence, SEQ ID NO, or compound representedby a specific ION number, or portion thereof. In certain embodiments,compounds described herein are antisense compounds or oligomericcompounds. In certain embodiments, compounds described herein aremodified oligonucleotides. As used herein, a compound is identical tothe sequence disclosed herein if it has the same nucleobase pairingability. For example, a RNA which contains uracil in place of thymidinein a disclosed DNA sequence would be considered identical to the DNAsequence since both uracil and thymidine pair with adenine. Shortenedand lengthened versions of the compounds described herein as well ascompounds having non-identical bases relative to the compounds providedherein also are contemplated. The non-identical bases may be adjacent toeach other or dispersed throughout the compound. Percent identity of ancompound is calculated according to the number of bases that haveidentical base pairing relative to the sequence to which it is beingcompared.

In certain embodiments, compounds described herein, or portions thereof,are, or are at least, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99% or 100% identical to one or more of the compounds orSEQ ID NOs, or a portion thereof, disclosed herein. In certainembodiments, compounds described herein are about 70%, 75%, 80%, 85%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical, or anypercentage between such values, to a particular nucleotide sequence, SEQID NO, or compound represented by a specific ION number, or portionthereof, in which the compounds comprise an oligonucleotide having oneor more mismatched nucleobases. In certain such embodiments, themismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 fromthe 5′-end of the oligonucleotide. In certain such embodiments, themismatch is at position, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 from the3′-end of the oligonucleotide.

In certain embodiments, compounds described herein comprise or consistof antisense compounds. In certain embodiments, a portion of theantisense compound is compared to an equal length portion of the targetnucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is comparedto an equal length portion of the target nucleic acid.

In certain embodiments, compounds described herein comprise or consistof oligonucleotides. In certain embodiments, a portion of theoligonucleotide is compared to an equal length portion of the targetnucleic acid. In certain embodiments, an 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 nucleobase portion is comparedto an equal length portion of the target nucleic acid.

Certain Modified Compounds

In certain embodiments, compounds described herein comprise or consistof oligonucleotides consisting of linked nucleosides. Oligonucleotidesmay be unmodified oligonucleotides (RNA or DNA) or may be modifiedoligonucleotides. Modified oligonucleotides comprise at least onemodification relative to unmodified RNA or DNA (i.e., comprise at leastone modified nucleoside (comprising a modified sugar moiety and/or amodified nucleobase) and/or at least one modified internucleosidelinkage).

A. Modified Nucleosides

Modified nucleosides comprise a modified sugar moiety or a modifiednucleobase or both a modified sugar moiety and a modified nucleobase.

1. Modified Sugar Moieties

In certain embodiments, sugar moieties are non-bicyclic modified sugarmoieties. In certain embodiments, modified sugar moieties are bicyclicor tricyclic sugar moieties. In certain embodiments, modified sugarmoieties are sugar surrogates. Such sugar surrogates may comprise one ormore substitutions corresponding to those of other types of modifiedsugar moieties.

In certain embodiments, modified sugar moieties are non-bicyclicmodified furanosyl sugar moieties comprising one or more acyclicsubstituent, including, but not limited, to substituents at the 2′, 4′,and/or 5′ positions. In certain embodiments, the furanosyl sugar moietyis a ribosyl sugar moiety. In certain embodiments, one or more acyclicsubstituent of non-bicyclic modified sugar moieties is branched.Examples of 2′-substituent groups suitable for non-bicyclic modifiedsugar moieties include but are not limited to: 2′-F, 2′-OCH₃ (“OMe” or“O-methyl”), and 2′-O(CH₂)₂OCH₃ (“MOE”). In certain embodiments,2′-substituent groups are selected from among: halo, allyl, amino,azido, SH, CN, OCN, CF₃, OCF₃, O—C₁-C₁₀ alkoxy, O—C₁-C₁₀ substitutedalkoxy, O—C₁-C₁₀ alkyl, O—C₁-C₁₀ substituted alkyl, S-alkyl,N(R_(m))-alkyl, O-alkenyl, S-alkenyl, N(R_(m))-alkenyl, O-alkynyl,S-alkynyl, N(R_(m))-alkynyl, O-alkylenyl-O-alkyl, alkynyl, alkaryl,aralkyl, O-alkaryl, O-aralkyl, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_(m))(R_(n)) orOCH₂C(═O)—N(R_(m))(R_(n)), where each R_(m) and R_(n) is, independently,H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀alkyl, and the 2′-substituent groups described in Cook et al., U.S. Pat.No. 6,531,584; Cook et al., U.S. Pat. No. 5,859,221; and Cook et al.,U.S. Pat. No. 6,005,087. Certain embodiments of these 2′-substituentgroups can be further substituted with one or more substituent groupsindependently selected from among: hydroxyl, amino, alkoxy, carboxy,benzyl, phenyl, nitro (NO₂), thiol, thioalkoxy, thioalkyl, halogen,alkyl, aryl, alkenyl and alkynyl. Examples of 4′-substituent groupssuitable for linearly non-bicyclic modified sugar moieties include, butare not limited to, alkoxy (e.g., methoxy), alkyl, and those describedin Manoharan et al., WO 2015/106128. Examples of 5′-substituent groupssuitable for non-bicyclic modified sugar moieties include, but are notlimited to: 5′-methyl (R or S), 5′-vinyl, and 5′-methoxy. In certainembodiments, non-bicyclic modified sugars comprise more than onenon-bridging sugar substituent, for example, 2′-F-5′-methyl sugarmoieties and the modified sugar moieties and modified nucleosidesdescribed in Migawa et al., WO 2008/101157 and Rajeev et al.,US2013/0203836.

In certain embodiments, a 2′-substituted nucleoside or 2′-non-bicyclicmodified nucleoside comprises a sugar moiety comprising a linear2′-substituent group selected from: F, NH₂, N₃, OCF₃, OCH₃, O(CH₂)₃NH₂,CH₂CH═CH₂, OCH₂CH═CH₂, OCH₂CH₂OCH₃, O(CH₂)₂SCH₃,O(CH₂)₂ON(R_(m))(R_(n)), O(CH₂)₂O(CH₂)₂N(CH₃)₂, and N-substitutedacetamide (OCH₂C(═O)—N(R_(m))(R_(n)), where each R_(m) and R_(n) is,independently, H, an amino protecting group, or substituted orunsubstituted C₁-C₁₀ alkyl.

In certain embodiments, a 2′-substituted nucleoside or 2′-non-bicyclicmodified nucleoside comprises a sugar moiety comprising a linear2′-substituent group selected from: F, OCF₃, OCH₃, OCH₂CH₂OCH₃,O(CH₂)₂SCH₃, O(CH₂)₂ON(CH₃)₂, O(CH₂)₂O(CH₂)₂N(CH₃)₂, andOCH₂C(═O)—N(H)CH₃ (“NMA”).

In certain embodiments, a 2′-substituted nucleoside or 2′-non-bicyclicmodified nucleoside comprises a sugar moiety comprising a linear2′-substituent group selected from: F, OCH₃, and OCH₂CH₂OCH₃.

Nucleosides comprising modified sugar moieties, such as non-bicyclicmodified sugar moieties, are referred to by the position(s) of thesubstitution(s) on the sugar moiety of the nucleoside. For example,nucleosides comprising 2′-substituted or 2′-modified sugar moieties arereferred to as 2′-substituted nucleosides or 2′-modified nucleosides.

Certain modified sugar moieties comprise a bridging sugar substituentthat forms a second ring resulting in a bicyclic sugar moiety. Incertain such embodiments, the bicyclic sugar moiety comprises a bridgebetween the 4′ and the 2′ furanose ring atoms. In certain suchembodiments, the furanose ring is a ribose ring. Examples of such 4′ to2′ bridging sugar substituents include, but are not limited to:4′-CH₂-2′, 4′-(CH₂)₂-2′, 4′-(CH₂)₃-2′, 4′-CH₂—O-2′ (“LNA”), 4′-CH₂—S-2′,4′-(CH₂)₂—O-2′ (“ENA”), 4′-CH(CH₃)—O-2′ (referred to as “constrainedethyl” or “cEt” when in the S configuration), 4′-CH₂—O—CH₂-2′,4′-CH₂—N(R)-2′, 4′-CH(CH₂OCH₃)—O-2′ (“constrained MOE” or “cMOE”) andanalogs thereof (see, e.g., Seth et al., U.S. Pat. No. 7,399,845, Bhatet al., U.S. Pat. No. 7,569,686, Swayze et al., U.S. Pat. No. 7,741,457,and Swayze et al., U.S. Pat. No. 8,022,193), 4′-C(CH₃)(CH₃)—O-2′ andanalogs thereof (see, e.g., Seth et al., U.S. Pat. No. 8,278,283),4′-CH₂—N(OCH₃)-2′ and analogs thereof (see, e.g., Prakash et al., U.S.Pat. No. 8,278,425), 4′-CH₂—O—N(CH₃)-2′ (see, e.g., Allerson et al.,U.S. Pat. No. 7,696,345 and Allerson et al., U.S. Pat. No. 8,124,745),4′-CH₂—C(H)(CH₃)-2′ (see, e.g., Zhou, et al., J. Org. Chem., 2009, 74,118-134), 4′-CH₂—C(═CH₂)-2′ and analogs thereof (see e.g., Seth et al.,U.S. Pat. No. 8,278,426), 4′-C(R_(a)R_(b))—N(R)—O-2′,4′-C(R_(a)R_(b))—O—N(R)-2′, 4′-CH₂—O—N(R)-2′, and 4′-CH₂—N(R)—O-2′,wherein each R, R_(a), and R_(b) is, independently, H, a protectinggroup, or C₁-C₁₂ alkyl (see, e.g. Imanishi et al., U.S. Pat. No.7,427,672).

In certain embodiments, such 4′ to 2′ bridges independently comprisefrom 1 to 4 linked groups independently selected from:—[C(R_(a))(R_(b))]_(n)—, —[C(R_(a))(R_(b))]_(n)—O—, —C(R_(n))═C(R_(b))—,—C(R_(a))═N—, —C(═NR_(a))—, —C(═O)—, —C(═S)—, —O—, —Si(R_(a))₂—,—S(═O)_(x)—, and —N(R_(a))—;

wherein:

x is 0, 1, or 2;

n is 1, 2, 3, or 4;

each R_(a) and R_(b) is, independently, H, a protecting group, hydroxyl,C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substitutedC₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl,substituted C₅-C₂₀ aryl, heterocycle radical, substituted heterocycleradical, heteroaryl, substituted heteroaryl, C₅-C₇ alicyclic radical,substituted C₅-C₇ alicyclic radical, halogen, OJ₁, NJ₁J₂, SJ₁, N₃,COOJ₁, acyl (C(═O)—H), substituted acyl, CN, sulfonyl (S(═O)₂-J₁), orsulfoxyl (S(═O)-J₁); and each J₁ and J₂ is, independently, H, C₁-C₁₂alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl,substituted C₅-C₂₀ aryl, acyl (C(═O)—H), substituted acyl, a heterocycleradical, a substituted heterocycle radical, C₁-C₁₂ aminoalkyl,substituted C₁-C₁₂ aminoalkyl, or a protecting group.

Additional bicyclic sugar moieties are known in the art, see, forexample: Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443,Albaek et al., J. Org. Chem., 2006, 71, 7731-7740, Singh et al., Chem.Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54,3607-3630; Wahlestedt et al., Proc. Natl. Acad. Sci. U S. A., 2000, 97,5633-5638; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222;Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Srivastava et al.,J. Am. Chem. Soc., 2007, 129, 8362-8379; Elayadi et al., Curr. OpinionInvens. Drugs, 2001, 2, 558-561; Braasch et al., Chem. Biol., 2001, 8,1-7; Orum et al., Curr. Opinion Mol. Ther., 2001, 3, 239-243; Wengel etal., U.S. Pat. No. 7,053,207, Imanishi et al., U.S. Pat. No. 6,268,490,Imanishi et al. U.S. Pat. No. 6,770,748, Imanishi et al., U.S. RE44,779;Wengel et al., U.S. Pat. No. 6,794,499, Wengel et al., U.S. Pat. No.6,670,461; Wengel et al., U.S. Pat. No. 7,034,133, Wengel et al., U.S.Pat. No. 8,080,644; Wengel et al., U.S. Pat. No. 8,034,909; Wengel etal., U.S. Pat. No. 8,153,365; Wengel et al., U.S. Pat. No. 7,572,582;and Ramasamy et al., U.S. Pat. No. 6,525,191, Torsten et al., WO2004/106356, Wengel et al., WO 1999/014226; Seth et al., WO 2007/134181;Seth et al., U.S. Pat. No. 7,547,684; Seth et al., U.S. Pat. No.7,666,854; Seth et al., U.S. Pat. No. 8,088,746; Seth et al., U.S. Pat.No. 7,750,131; Seth et al., U.S. Pat. No. 8,030,467; Seth et al., U.S.Pat. No. 8,268,980; Seth et al., U.S. Pat. No. 8,546,556; Seth et al.,U.S. Pat. No. 8,530,640; Migawa et al., U.S. Pat. No. 9,012,421; Seth etal., U.S. Pat. No. 8,501,805; Allerson et al., US2008/0039618; andMigawa et al., US2015/0191727.

In certain embodiments, bicyclic sugar moieties and nucleosidesincorporating such bicyclic sugar moieties are further defined byisomeric configuration. For example, an LNA nucleoside (describedherein) may be in the α-L configuration or in the β-D configuration.

α-L-methyleneoxy (4′-CH₂—O-2′) or α-L-LNA bicyclic nucleosides have beenincorporated into oligonucleotides that showed antisense activity(Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372). Herein,general descriptions of bicyclic nucleosides include both isomericconfigurations. When the positions of specific bicyclic nucleosides(e.g., LNA or cEt) are identified in exemplified embodiments herein,they are in the β-D configuration, unless otherwise specified.

In certain embodiments, modified sugar moieties comprise one or morenon-bridging sugar substituent and one or more bridging sugarsubstituent (e.g., 5′-substituted and 4′-2′ bridged sugars).

In certain embodiments, modified sugar moieties are sugar surrogates. Incertain such embodiments, the oxygen atom of the sugar moiety isreplaced, e.g., with a sulfur, carbon or nitrogen atom. In certain suchembodiments, such modified sugar moieties also comprise bridging and/ornon-bridging substituents as described herein. For example, certainsugar surrogates comprise a 4′-sulfur atom and a substitution at the2′-position (see, e.g., Bhat et al., U.S. Pat. No. 7,875,733 and Bhat etal., U.S. Pat. No. 7,939,677) and/or the 5′ position.

In certain embodiments, sugar surrogates comprise rings having otherthan 5 atoms. For example, in certain embodiments, a sugar surrogatecomprises a six-membered tetrahydropyran (“THP”). Such tetrahydropyransmay be further modified or substituted. Nucleosides comprising suchmodified tetrahydropyrans include, but are not limited to, hexitolnucleic acid (“HNA”), anitol nucleic acid (“ANA”), manitol nucleic acid(“MNA”) (see e.g., Leumann, C J. Bioorg. & Med. Chem. 2002, 10,841-854), fluoro HNA:

(“F-HNA”, see e.g., Swayze et al., U.S. Pat. No. 8,088,904; Swayze etal., U.S. Pat. No. 8,440,803; and Swayze et al., U.S. 9,005,906) F-HNAcan also be referred to as a F-THP or 3′-fluoro tetrahydropyran, andnucleosides comprising additional modified THP compounds having theformula:

wherein, independently, for each of said modified THP nucleoside:

Bx is a nucleobase moiety;

T₃ and T₄ are each, independently, an internucleoside linking grouplinking the modified THP nucleoside to the remainder of anoligonucleotide or one of T₃ and T₄ is an internucleoside linking grouplinking the modified THP nucleoside to the remainder of anoligonucleotide and the other of T₃ and T₄ is H, a hydroxyl protectinggroup, a linked conjugate group, or a 5′ or 3′-terminal group; q₁, q₂,q₃, q₄, q₅, q₆ and q₇ are each, independently, H, C₁-C₆ alkyl,substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆alkynyl, or substituted C₂-C₆ alkynyl; and each of R₁ and R₂ isindependently selected from among: hydrogen, halogen, substituted orunsubstituted alkoxy, NJ₁J₂, SJ₁, N₃, OC(═X)J₁, OC(═X)NJ₁J₂,NJ₃C(═X)NJ₁J₂, and CN, wherein X is O, S or NJ₁, and each J₁, J₂, and J₃is, independently, H or C₁-C₆ alkyl.

In certain embodiments, modified THP nucleosides are provided whereinq₁, q₂, q₃, q₄, q₅, q₆ and q₇ are each H. In certain embodiments, atleast one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is other than H. In certainembodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is methyl. Incertain embodiments, modified THP nucleosides are provided wherein oneof R₁ and R₂ is F. In certain embodiments, R₁ is F and R₂ is H, incertain embodiments, R₁ is methoxy and R₂ is H, and in certainembodiments, R₁ is methoxyethoxy and R₂ is H.

In certain embodiments, sugar surrogates comprise rings having more than5 atoms and more than one heteroatom. For example, nucleosidescomprising morpholino sugar moieties and their use in oligonucleotideshave been reported (see, e.g., Braasch et al., Biochemistry, 2002, 41,4503-4510 and Summerton et al., U.S. Pat. No. 5,698,685; Summerton etal., U.S. Pat. No. 5,166,315; Summerton et al., U.S. Pat. No. 5,185,444;and Summerton et al., U.S. Pat. No. 5,034,506). As used here, the term“morpholino” means a sugar surrogate having the following structure:

In certain embodiments, morpholinos may be modified, for example, byadding or altering various substituent groups from the above morpholinostructure. Such sugar surrogates are referred to herein as “modifiedmorpholinos.”

In certain embodiments, sugar surrogates comprise acyclic moieties.Examples of nucleosides and oligonucleotides comprising such acyclicsugar surrogates include, but are not limited to: peptide nucleic acid(“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org.Biomol. Chem., 2013, 11, 5853-5865), and nucleosides andoligonucleotides described in Manoharan et al., US2013/130378.

Many other bicyclic and tricyclic sugar and sugar surrogate ring systemsare known in the art that can be used in modified nucleosides.

In certain embodiments, modified oligonucleotides comprise a 2′-OMemodified nucleoside in the gap of a cEt gapmer. In certain embodiments,the 2′-OMe modified nucleoside is at position 2 or 3 of the gap. Incertain embodiments, the 2′-OMe modified nucleoside is at position 2 ofthe gap. In certain embodiments, modified oligonucleotides have a sugarmotif kkkdmddddddddkkk, wherein each k represents a cEt nucleoside, eachd represents a 2′-β-D-deoxyribosyl mucleoside, and each m represents anucleoside comprising a 2′-OMe sugar moiety (“2′-OMe nucleoside”).

In certain embodiments, modified oligonucleotides have a formula A-B-C,wherein A is a 5′-region, B is a central region, and C is a 3′-region.In certain embodiments, A and C each consist of 1-5 linked nucleosidesand B consists of 7-11 linked nucleosides. In certain embodiments, A andC consist of 3 linked cEt nucleosides. In certain embodiments, thesecond nucleoside of the central region comprises a 2′-OMe modifiedsugar moiety, and each of the remaining central region nucleosidescomprises a 2′-β-D-deoxyribosyl sugar moiety.

In certain embodiments, modified oligonucleotides comprise a neutralphosphonate linkage at one or more positions. In certain embodiments,modified oligonucleotides comprise a methoxypropyl phosphonate linkageat one or more positions. In certain embodiments, the sugar motif of amodified oligonucleotide is a gapmer, and the internucleoside linkagemotif comprises at least one methoxypropyl phosphonate linkage in thegap. In certain embodiments, the methoxypropyl phosphonate linkage isbetween the second and third nucleosides in the gap. In certainembodiments, the methoxypropyl phosphonate linkage is between the thirdand fourth nucleosides in the gap.

2. Modified Nucleobases

Nucleobase (or base) modifications or substitutions are structurallydistinguishable from, yet functionally interchangeable with, naturallyoccurring or synthetic unmodified nucleobases. Both natural and modifiednucleobases are capable of participating in hydrogen bonding. Suchnucleobase modifications can impart nuclease stability, binding affinityor some other beneficial biological property to antisense compounds.

In certain embodiments, compounds described herein comprise modifiedoligonucleotides. In certain embodiments, modified oligonucleotidescomprise one or more nucleoside comprising an unmodified nucleobase. Incertain embodiments, modified oligonucleotides comprise one or morenucleoside comprising a modified nucleobase. In certain embodiments,modified oligonucleotides comprise one or more nucleosides that does notcomprise a nucleobase, referred to as an abasic nucleoside.

In certain embodiments, modified nucleobases are selected from:5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynylsubstituted pyrimidines, alkyl substituted purines, and N-2, N-6 and 0-6substituted purines. In certain embodiments, modified nucleobases areselected from: 2-aminopropyladenine, 5-hydroxymethyl cytosine,5-methylcytosine, xanthine, hypoxanthine, 2-aminoadenine,6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil,2-thiothymine and 2-thiocytosine, 5-propynyl (C≡C—CH₃) uracil,5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine,5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol,8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo,particularly, 5-bromo, 5-trifluoromethyl, 5-halouracil, and5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine,2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine,3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine,4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine,5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases,promiscuous bases, size-expanded bases, and fluorinated bases. Furthermodified nucleobases include tricyclic pyrimidines, such as1,3-diazaphenoxazine-2-one, 1,3-diazaphenothiazine-2-one, and9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp). Modifiednucleobases may also include those in which the purine or pyrimidinebase is replaced with other heterocycles, for example, 7-deaza-adenine,7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobasesinclude those disclosed in Merigan et al., U.S. Pat. No. 3,687,808,those disclosed in The Concise Encyclopedia Of Polymer Science AndEngineering, Kroschwitz, J. I., Ed., John Wiley & Sons, 1990, 858-859;Englisch et al., Angewandte Chemie, International Edition, 1991, 30,613; Sanghvi, Y. S., Chapter 15, Antisense Research and Applications,Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; and thosedisclosed in Chapters 6 and 15, Antisense Drug Technology, Crooke S. T.,Ed., CRC Press, 2008, 163-166 and 442-443.

Publications that teach the preparation of certain of the above notedmodified nucleobases, as well as other modified nucleobases includewithout limitation, Manoharan et al., US2003/0158403, Manoharan et al.,US2003/0175906; Dinh et al., U.S. Pat. No. 4,845,205; Spielvogel et al.,U.S. Pat. No. 5,130,302; Rogers et al., U.S. Pat. No. 5,134,066;Bischofberger et al., U.S. Pat. No. 5,175,273; Urdea et al., U.S. Pat.No. 5,367,066; Benner et al., U.S. Pat. No. 5,432,272; Matteucci et al.,U.S. Pat. No. 5,434,257; Gmeiner et al., U.S. Pat. No. 5,457,187; Cooket al., U.S. Pat. No. 5,459,255; Froehler et al., U.S. Pat. No.5,484,908; Matteucci et al., U.S. Pat. No. 5,502,177; Hawkins et al.,U.S. Pat. No. 5,525,711; Haralambidis et al., U.S. Pat. No. 5,552,540;Cook et al., U.S. Pat. No. 5,587,469; Froehler et al., U.S. Pat. No.5,594,121; Switzer et al., U.S. Pat. No. 5,596,091; Cook et al., U.S.Pat. No. 5,614,617; Froehler et al., U.S. Pat. No. 5,645,985; Cook etal., U.S. Pat. No. 5,681,941; Cook et al., U.S. Pat. No. 5,811,534; Cooket al., U.S. Pat. No. 5,750,692; Cook et al., U.S. Pat. No. 5,948,903;Cook et al., U.S. Pat. No. 5,587,470; Cook et al., U.S. Pat. No.5,457,191; Matteucci et al., U.S. Pat. No. 5,763,588; Froehler et al.,U.S. Pat. No. 5,830,653; Cook et al., U.S. Pat. No. 5,808,027; Cook etal., U.S. Pat. No. 6,166,199; and Matteucci et al., U.S. Pat. No.6,005,096.

In certain embodiments, compounds targeted to a HSD17B13 nucleic acidcomprise one or more modified nucleobases. In certain embodiments, themodified nucleobase is 5-methylcytosine. In certain embodiments, eachcytosine is a 5-methylcytosine.

Modified Internucleoside Linkages

The naturally occurring internucleoside linkage of RNA and DNA is a 3′to 5′ phosphodiester linkage. In certain embodiments, compoundsdescribed herein having one or more modified, i.e. non-naturallyoccurring, internucleoside linkages are often selected over compoundshaving naturally occurring internucleoside linkages because of desirableproperties such as, for example, enhanced cellular uptake, enhancedaffinity for target nucleic acids, and increased stability in thepresence of nucleases.

Representative internucleoside linkages having a chiral center includebut are not limited to alkylphosphonates and phosphorothioates. Modifiedoligonucleotides comprising internucleoside linkages having a chiralcenter can be prepared as populations of modified oligonucleotidescomprising stereorandom internucleoside linkages, or as populations ofmodified oligonucleotides comprising phosphorothioate linkages inparticular stereochemical configurations. In certain embodiments,populations of modified oligonucleotides comprise phosphorothioateinternucleoside linkages wherein all of the phosphorothioateinternucleoside linkages are stereorandom. Such modifiedoligonucleotides can be generated using synthetic methods that result inrandom selection of the stereochemical configuration of eachphosphorothioate linkage. Nonetheless, as is well understood by those ofskill in the art, each individual phosphorothioate of each individualoligonucleotide molecule has a defined stereoconfiguration. In certainembodiments, populations of modified oligonucleotides are enriched formodified oligonucleotides comprising one or more particularphosphorothioate internucleoside linkages in a particular, independentlyselected stereochemical configuration. In certain embodiments, theparticular configuration of the particular phosphorothioate linkage ispresent in at least 65% of the molecules in the population. In certainembodiments, the particular configuration of the particularphosphorothioate linkage is present in at least 70% of the molecules inthe population. In certain embodiments, the particular configuration ofthe particular phosphorothioate linkage is present in at least 80% ofthe molecules in the population. In certain embodiments, the particularconfiguration of the particular phosphorothioate linkage is present inat least 90% of the molecules in the population. In certain embodiments,the particular configuration of the particular phosphorothioate linkageis present in at least 99% of the molecules in the population. Suchchirally enriched populations of modified oligonucleotides can begenerated using synthetic methods known in the art, e.g., methodsdescribed in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid.Res. 42, 13456 (2014), and WO 2017/015555. In certain embodiments, apopulation of modified oligonucleotides is enriched for modifiedoligonucleotides having at least one indicated phosphorothioate in the(Sp) configuration. In certain embodiments, a population of modifiedoligonucleotides is enriched for modified oligonucleotides having atleast one phosphorothioate in the (Rp) configuration. In certainembodiments, modified oligonucleotides comprising (Rp) and/or (Sp)phosphorothioates comprise one or more of the following formulas,respectively, wherein “B” indicates a nucleobase:

Unless otherwise indicated, chiral internucleoside linkages of modifiedoligonucleotides described herein can be stereorandom or in a particularstereochemical configuration.

In certain embodiments, compounds targeted to a HSD17B13 nucleic acidcomprise one or more modified internucleoside linkages. In certainembodiments, the modified internucleoside linkages are phosphorothioatelinkages. In certain embodiments, each internucleoside linkage of anantisense compound is a phosphorothioate internucleoside linkage.

In certain embodiments, compounds described herein compriseoligonucleotides. Oligonucleotides having modified internucleosidelinkages include internucleoside linkages that retain a phosphorus atomas well as internucleoside linkages that do not have a phosphorus atom.Representative phosphorus containing internucleoside linkages include,but are not limited to, phosphodiesters, phosphotriesters,methylphosphonates, phosphoramidate, and phosphorothioates. Methods ofpreparation of phosphorous-containing and non-phosphorous-containinglinkages are well known.

In certain embodiments, nucleosides of modified oligonucleotides may belinked together using any internucleoside linkage. The two main classesof internucleoside linking groups are defined by the presence or absenceof a phosphorus atom. Representative phosphorus-containinginternucleoside linkages include, but are not limited to, phosphates,which contain a phosphodiester bond (“P═O”) (also referred to asunmodified or naturally occurring linkages), phosphotriesters,methylphosphonates, phosphoramidates, and phosphorothioates (“P═S”), andphosphorodithioates (“HS—P═S”). Representative non-phosphorus containinginternucleoside linking groups include, but are not limited to,methylenemethylimino (—CH₂—N(CH₃)—O—CH₂), thiodiester, thionocarbamate(—O—C(═O)(NH)—S—); siloxane (—O—SiH₂—O—); and N,N′-dimethylhydrazine(—CH₂—N(CH₃)—N(CH₃)—). Modified internucleoside linkages, compared tonaturally occurring phosphate linkages, can be used to alter, typicallyincrease, nuclease resistance of the oligonucleotide. In certainembodiments, internucleoside linkages having a chiral atom can beprepared as a racemic mixture, or as separate enantiomers.Representative chiral internucleoside linkages include, but are notlimited to, alkylphosphonates and phosphorothioates. Methods ofpreparation of phosphorous-containing and non-phosphorous-containinginternucleoside linkages are well known to those skilled in the art.

Neutral internucleoside linkages include, without limitation,phosphotriesters, methylphosphonates, MMI (3′-CH₂—N(CH₃)—O-5′), amide-3(3′-CH₂—C(═O)—N(H)-5′), amide-4 (3′-CH₂—N(H)—C(═O)-5′), formacetal(3′-O—CH₂—O-5′), methoxypropyl, and thioformacetal (3′-S—CH₂—O-5′).Further neutral internucleoside linkages include nonionic linkagescomprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide,sulfide, sulfonate ester and amides (See, for example: CarbohydrateModifications in Antisense Research; Y. S. Sanghvi and P. D. Cook, Eds.,ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutralinternucleoside linkages include nonionic linkages comprising mixed N,O, S and CH₂ component parts.

In certain embodiments, oligonucleotides comprise modifiedinternucleoside linkages arranged along the oligonucleotide or regionthereof in a defined pattern or modified internucleoside linkage motif.In certain embodiments, internucleoside linkages are arranged in agapped motif. In such embodiments, the internucleoside linkages in eachof two wing regions are different from the internucleoside linkages inthe gap region. In certain embodiments, the internucleoside linkages inthe wings are phosphodiester and the internucleoside linkages in the gapare phosphorothioate. The nucleoside motif is independently selected, sosuch oligonucleotides having a gapped internucleoside linkage motif mayor may not have a gapped nucleoside motif and, if it does have a gappednucleoside motif, the wing and gap lengths may or may not be the same.

In certain embodiments, oligonucleotides comprise a region having analternating internucleoside linkage motif. In certain embodiments,oligonucleotides comprise a region of uniformly modified internucleosidelinkages. In certain such embodiments, the oligonucleotide comprises aregion that is uniformly linked by phosphorothioate internucleosidelinkages. In certain embodiments, the oligonucleotide is uniformlylinked by phosphorothioate. In certain embodiments, each internucleosidelinkage of the oligonucleotide is selected from phosphodiester andphosphorothioate. In certain embodiments, each internucleoside linkageof the oligonucleotide is selected from phosphodiester andphosphorothioate and at least one internucleoside linkage isphosphorothioate.

In certain embodiments, the oligonucleotide comprises at least 6phosphorothioate internucleoside linkages. In certain embodiments, theoligonucleotide comprises at least 8 phosphorothioate internucleosidelinkages. In certain embodiments, the oligonucleotide comprises at least10 phosphorothioate internucleoside linkages. In certain embodiments,the oligonucleotide comprises at least one block of at least 6consecutive phosphorothioate internucleoside linkages. In certainembodiments, the oligonucleotide comprises at least one block of atleast 8 consecutive phosphorothioate internucleoside linkages. Incertain embodiments, the oligonucleotide comprises at least one block ofat least 10 consecutive phosphorothioate internucleoside linkages. Incertain embodiments, the oligonucleotide comprises at least block of atleast one 12 consecutive phosphorothioate internucleoside linkages. Incertain such embodiments, at least one such block is located at the 3′end of the oligonucleotide. In certain such embodiments, at least onesuch block is located within 3 nucleosides of the 3′ end of theoligonucleotide.

In certain embodiments, oligonucleotides comprise one or moremethylphosphonate linkages. In certain embodiments, oligonucleotideshaving a gapmer nucleoside motif comprise a linkage motif comprising allphosphorothioate linkages except for one or two methylphosphonatelinkages. In certain embodiments, one methylphosphonate linkage is inthe central gap of an oligonucleotide having a gapmer nucleoside motif.

In certain embodiments, it is desirable to arrange the number ofphosphorothioate internucleoside linkages and phosphodiesterinternucleoside linkages to maintain nuclease resistance. In certainembodiments, it is desirable to arrange the number and position ofphosphorothioate internucleoside linkages and the number and position ofphosphodiester internucleoside linkages to maintain nuclease resistance.In certain embodiments, the number of phosphorothioate internucleosidelinkages may be decreased and the number of phosphodiesterinternucleoside linkages may be increased. In certain embodiments, thenumber of phosphorothioate internucleoside linkages may be decreased andthe number of phosphodiester internucleoside linkages may be increasedwhile still maintaining nuclease resistance. In certain embodiments, itis desirable to decrease the number of phosphorothioate internucleosidelinkages while retaining nuclease resistance. In certain embodiments, itis desirable to increase the number of phosphodiester internucleosidelinkages while retaining nuclease resistance.

3. Certain Motifs

In certain embodiments, compounds described herein compriseoligonucleotides. Oligonucleotides can have a motif, e.g. a pattern ofunmodified and/or modified sugar moieties, nucleobases, and/orinternucleoside linkages. In certain embodiments, modifiedoligonucleotides comprise one or more modified nucleosides comprising amodified sugar. In certain embodiments, modified oligonucleotidescomprise one or more modified nucleosides comprising a modifiednucleobase. In certain embodiments, modified oligonucleotides compriseone or more modified internucleoside linkage. In such embodiments, themodified, unmodified, and differently modified sugar moieties,nucleobases, and/or internucleoside linkages of a modifiedoligonucleotide define a pattern or motif. In certain embodiments, thepatterns of sugar moieties, nucleobases, and internucleoside linkagesare each independent of one another. Thus, a modified oligonucleotidemay be described by its sugar motif, nucleobase motif and/orinternucleoside linkage motif (as used herein, nucleobase motifdescribes the modifications to the nucleobases independent of thesequence of nucleobases).

a. Certain Sugar Motifs

In certain embodiments, compounds described herein compriseoligonucleotides. In certain embodiments, oligonucleotides comprise oneor more type of modified sugar and/or unmodified sugar moiety arrangedalong the oligonucleotide or region thereof in a defined pattern orsugar motif. In certain instances, such sugar motifs include, but arenot limited to, any of the sugar modifications discussed herein.

In certain embodiments, modified oligonucleotides comprise or consist ofa region having a gapmer motif, which comprises two external regions or“wings” and a central or internal region or “gap”. The three regions ofa gapmer motif (the 5′-wing, the gap, and the 3′-wing) form a contiguoussequence of nucleosides, wherein at least some of the sugar moieties ofthe nucleosides of each of the wings differ from at least some of thesugar moieties of the nucleosides of the gap. Specifically, at least thesugar moieties of the nucleosides of each wing that are closest to thegap (the 3′-most nucleoside of the 5′-wing and the 5′-most nucleoside ofthe 3′-wing) differ from the sugar moiety of the neighboring gapnucleosides, thus defining the boundary between the wings and the gap(i.e., the wing/gap junction). In certain embodiments, the sugarmoieties within the gap are the same as one another. In certainembodiments, the gap includes one or more nucleosides having a sugarmoiety that differs from the sugar moiety of one or more othernucleosides of the gap. In certain embodiments, the sugar motifs of thetwo wings are the same as one another (symmetric gapmer). In certainembodiments, the sugar motif of the 5′-wing differs from the sugar motifof the 3′-wing (asymmetric gapmer).

In certain embodiments, the wings of a gapmer comprise 1-5 nucleosides.In certain embodiments, the wings of a gapmer comprise 2-5 nucleosides.In certain embodiments, the wings of a gapmer comprise 3-5 nucleosides.In certain embodiments, the nucleosides of a gapmer are all modifiednucleosides.

In certain embodiments, the gap of a gapmer comprises 7-12 nucleosides.In certain embodiments, the gap of a gapmer comprises 7-10 nucleosides.In certain embodiments, the gap of a gapmer comprises 8-10 nucleosides.In certain embodiments, the gap of a gapmer comprises 10 nucleosides. Incertain embodiments, each nucleoside of the gap of a gapmer is anunmodified 2′-deoxy nucleoside.

In certain embodiments, the gapmer is a deoxy gapmer. In suchembodiments, the nucleosides on the gap side of each wing/gap junctionare unmodified 2′-deoxy nucleosides and the nucleosides on the wingsides of each wing/gap junction are modified nucleosides. In certainsuch embodiments, each nucleoside of the gap is an unmodified 2′-deoxynucleoside. In certain such embodiments, each nucleoside of each wing isa modified nucleoside.

In certain embodiments, a modified oligonucleotide has a fully modifiedsugar motif wherein each nucleoside of the modified oligonucleotidecomprises a modified sugar moiety. In certain embodiments, modifiedoligonucleotides comprise or consist of a region having a fully modifiedsugar motif wherein each nucleoside of the region comprises a modifiedsugar moiety. In certain embodiments, modified oligonucleotides compriseor consist of a region having a fully modified sugar motif, wherein eachnucleoside within the fully modified region comprises the same modifiedsugar moiety, referred to herein as a uniformly modified sugar motif. Incertain embodiments, a fully modified oligonucleotide is a uniformlymodified oligonucleotide. In certain embodiments, each nucleoside of auniformly modified comprises the same 2′-modification.

b. Certain Nucleobase Motifs

In certain embodiments, compounds described herein compriseoligonucleotides. In certain embodiments, oligonucleotides comprisemodified and/or unmodified nucleobases arranged along theoligonucleotide or region thereof in a defined pattern or motif. Incertain embodiments, each nucleobase is modified. In certainembodiments, none of the nucleobases are modified. In certainembodiments, each purine or each pyrimidine is modified. In certainembodiments, each adenine is modified. In certain embodiments, eachguanine is modified. In certain embodiments, each thymine is modified.In certain embodiments, each uracil is modified. In certain embodiments,each cytosine is modified. In certain embodiments, some or all of thecytosine nucleobases in a modified oligonucleotide are5-methylcytosines.

In certain embodiments, modified oligonucleotides comprise a block ofmodified nucleobases. In certain such embodiments, the block is at the3′-end of the oligonucleotide. In certain embodiments, the block iswithin 3 nucleosides of the 3′-end of the oligonucleotide. In certainembodiments, the block is at the 5′-end of the oligonucleotide. Incertain embodiments, the block is within 3 nucleosides of the 5′-end ofthe oligonucleotide.

In certain embodiments, oligonucleotides having a gapmer motif comprisea nucleoside comprising a modified nucleobase. In certain suchembodiments, one nucleoside comprising a modified nucleobase is in thecentral gap of an oligonucleotide having a gapmer motif. In certain suchembodiments, the sugar moiety of said nucleoside is a 2′-deoxyribosylmoiety. In certain embodiments, the modified nucleobase is selectedfrom: a 2-thiopyrimidine and a 5-propynepyrimidine.

c. Certain Internucleoside Linkage Motifs

In certain embodiments, compounds described herein compriseoligonucleotides. In certain embodiments, oligonucleotides comprisemodified and/or unmodified internucleoside linkages arranged along theoligonucleotide or region thereof in a defined pattern or motif. Incertain embodiments, essentially each internucleoside linking group is aphosphate internucleoside linkage (P═O). In certain embodiments, eachinternucleoside linking group of a modified oligonucleotide is aphosphorothioate (P═S). In certain embodiments, each internucleosidelinking group of a modified oligonucleotide is independently selectedfrom a phosphorothioate and phosphate internucleoside linkage. Incertain embodiments, the sugar motif of a modified oligonucleotide is agapmer and the internucleoside linkages within the gap are all modified.In certain such embodiments, some or all of the internucleoside linkagesin the wings are unmodified phosphate linkages. In certain embodiments,the terminal internucleoside linkages are modified. In certainembodiments, the sugar motif of a modified oligonucleotide is a gapmer,and the internucleoside linkage motif comprises at least onephosphodiester internucleoside linkage in at least one wing, wherein theat least one phosphodiester linkage is not a terminal internucleosidelinkage, and the remaining internucleoside linkages are phosphorothioateinternucleoside linkages. In certain such embodiments, all of thephosphorothioate linkages are stereorandom. In certain embodiments, allof the phosphorothioate linkages in the wings are (Sp)phosphorothioates, and the gap comprises at least one Sp, Sp, Rp motif.In certain embodiments, populations of modified oligonucleotides areenriched for modified oligonucleotides comprising such internucleosidelinkage motifs.

4. Certain Modified Oligonucleotides

In certain embodiments, compounds described herein comprise modifiedoligonucleotides. In certain embodiments, the above modifications(sugar, nucleobase, internucleoside linkage) are incorporated into amodified oligonucleotide. In certain embodiments, modifiedoligonucleotides are characterized by their modification, motifs, andoverall lengths. In certain embodiments, such parameters are eachindependent of one another. Thus, unless otherwise indicated, eachinternucleoside linkage of an oligonucleotide having a gapmer sugarmotif may be modified or unmodified and may or may not follow the gapmermodification pattern of the sugar modifications. For example, theinternucleoside linkages within the wing regions of a sugar gapmer maybe the same or different from one another and may be the same ordifferent from the internucleoside linkages of the gap region of thesugar motif. Likewise, such gapmer oligonucleotides may comprise one ormore modified nucleobases independent of the gapmer pattern of the sugarmodifications. Furthermore, in certain instances, an oligonucleotide isdescribed by an overall length or range and by lengths or length rangesof two or more regions (e.g., a regions of nucleosides having specifiedsugar modifications). In such circumstances, it may be possible toselect numbers for each range that result in an oligonucleotide havingan overall length falling outside the specified range. In suchcircumstances, both elements must be satisfied. For example, in certainembodiments, a modified oligonucleotide consists of 15-20 linkednucleosides and has a sugar motif consisting of three regions, A, B, andC, wherein region A consists of 2-6 linked nucleosides having aspecified sugar motif, region B consists of 6-10 linked nucleosideshaving a specified sugar motif, and region C consists of 2-6 linkednucleosides having a specified sugar motif. Such embodiments do notinclude modified oligonucleotides where A and C each consist of 6 linkednucleosides and B consists of 10 linked nucleosides (even though thosenumbers of nucleosides are permitted within the requirements for A, B,and C) because the overall length of such oligonucleotide will be 22,which exceeds the upper limit of the overall length of the modifiedoligonucleotide (20). Herein, if a description of an oligonucleotide issilent with respect to one or more parameters, such parameter is notlimited. Thus, a modified oligonucleotide described only as having agapmer sugar motif without further description may have any length,internucleoside linkage motif, and nucleobase motif. Unless otherwiseindicated, all modifications are independent of nucleobase sequence.

Certain Conjugated Compounds

In certain embodiments, the compounds described herein comprise orconsist of an oligonucleotide (modified or unmodified) and, optionally,one or more conjugate groups and/or terminal groups. Conjugate groupsconsist of one or more conjugate moiety and a conjugate linker whichlinks the conjugate moiety to the oligonucleotide. Conjugate groups maybe attached to either or both ends of an oligonucleotide and/or at anyinternal position. In certain embodiments, conjugate groups are attachedto the 2′-position of a nucleoside of a modified oligonucleotide. Incertain embodiments, conjugate groups that are attached to either orboth ends of an oligonucleotide are terminal groups. In certain suchembodiments, conjugate groups or terminal groups are attached at the 3′and/or 5′-end of oligonucleotides. In certain such embodiments,conjugate groups (or terminal groups) are attached at the 3′-end ofoligonucleotides. In certain embodiments, conjugate groups are attachednear the 3′-end of oligonucleotides. In certain embodiments, conjugategroups (or terminal groups) are attached at the 5′-end ofoligonucleotides. In certain embodiments, conjugate groups are attachednear the 5′-end of oligonucleotides.

In certain embodiments, the oligonucleotide is modified. In certainembodiments, the oligonucleotide of a compound has a nucleobase sequencethat is complementary to a target nucleic acid. In certain embodiments,oligonucleotides are complementary to a messenger RNA (mRNA). In certainembodiments, oligonucleotides are complementary to a pre-mRNA. Incertain embodiments, oligonucleotides are complementary to a sensetranscript.

Examples of terminal groups include but are not limited to conjugategroups, capping groups, phosphate moieties, protecting groups, modifiedor unmodified nucleosides, and two or more nucleosides that areindependently modified or unmodified.

In certain embodiments, oligonucleotides are covalently attached to oneor more conjugate groups. In certain embodiments, conjugate groupsmodify one or more properties of the attached oligonucleotide, includingbut not limited to pharmacodynamics, pharmacokinetics, stability,binding, absorption, tissue distribution, cellular distribution,cellular uptake, charge and clearance. In certain embodiments, conjugategroups impart a new property on the attached oligonucleotide, e.g.,fluorophores or reporter groups that enable detection of theoligonucleotide. Certain conjugate groups and conjugate moieties havebeen described previously, for example: cholesterol moiety (Letsinger etal., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid(Manoharan et al., Bioorg. Med. Chem. Lett., 1994, 4, 1053-1060), athioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad.Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Lett.,1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl. AcidsRes., 1992, 20, 533-538), an aliphatic chain, e.g., do-decan-diol orundecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118;Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al.,Biochimie, 1993, 75, 49-54), a phospholipid, e.g.,di-hexadecyl-rac-glycerol or triethyl-ammonium1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al.,Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res.,1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain(Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), oradamantane acetic acid a palmityl moiety (Mishra et al., Biochim.Biophys. Acta, 1995, 1264, 229-237), an octadecylamine orhexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol.Exp. Ther., 1996, 277, 923-937), a tocopherol group (Nishina et al.,Molecular Therapy Nucleic Acids, 2015, 4, e220; and Nishina et al.,Molecular Therapy, 2008, 16, 734-740), or a GalNAc cluster (e.g.,WO2014/179620).

1. Conjugate Moieties

Conjugate moieties include, without limitation, intercalators, reportermolecules, polyamines, polyamides, peptides, carbohydrates (e.g.,GalNAc), vitamin moieties, polyethylene glycols, thioethers, polyethers,cholesterols, thiocholesterols, cholic acid moieties, folate, lipids,phospholipids, biotin, phenazine, phenanthridine, anthraquinone,adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores,and dyes.

In certain embodiments, a conjugate moiety comprises an active drugsubstance, for example, aspirin, warfarin, phenylbutazone, ibuprofen,suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen,dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid,folinic acid, a benzothiadiazide, chlorothiazide, a diazepine,indo-methicin, a barbiturate, a cephalosporin, a sulfa drug, anantidiabetic, an antibacterial or an antibiotic.

2. Conjugate Linkers

Conjugate moieties are attached to oligonucleotides through conjugatelinkers. In certain compounds, the conjugate linker is a single chemicalbond (i.e., the conjugate moiety is attached directly to anoligonucleotide through a single bond). In certain compounds, aconjugate moiety is attached to an oligonucleotide via a more complexconjugate linker comprising one or more conjugate linker moieities,which are sub-units making up a conjugate linker. In certainembodiments, the conjugate linker comprises a chain structure, such as ahydrocarbyl chain, or an oligomer of repeating units such as ethyleneglycol, nucleosides, or amino acid units.

In certain embodiments, a conjugate linker comprises one or more groupsselected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol,ether, thioether, and hydroxylamino. In certain such embodiments, theconjugate linker comprises groups selected from alkyl, amino, oxo, amideand ether groups. In certain embodiments, the conjugate linker comprisesgroups selected from alkyl and amide groups. In certain embodiments, theconjugate linker comprises groups selected from alkyl and ether groups.In certain embodiments, the conjugate linker comprises at least onephosphorus moiety. In certain embodiments, the conjugate linkercomprises at least one phosphate group. In certain embodiments, theconjugate linker includes at least one neutral linking group.

In certain embodiments, conjugate linkers, including the conjugatelinkers described above, are bifunctional linking moieties, e.g., thoseknown in the art to be useful for attaching conjugate groups to parentcompounds, such as the oligonucleotides provided herein. In general, abifunctional linking moiety comprises at least two functional groups.One of the functional groups is selected to bind to a particular site ona parent compound and the other is selected to bind to a conjugategroup. Examples of functional groups used in a bifunctional linkingmoiety include but are not limited to electrophiles for reacting withnucleophilic groups and nucleophiles for reacting with electrophilicgroups. In certain embodiments, bifunctional linking moieties compriseone or more groups selected from amino, hydroxyl, carboxylic acid,thiol, alkyl, alkenyl, and alkynyl.

Examples of conjugate linkers include but are not limited topyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) and6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include butare not limited to substituted or unsubstituted C₁-C₁₀ alkyl,substituted or unsubstituted C₂-C₁₀ alkenyl or substituted orunsubstituted C₂-C₁₀ alkynyl, wherein a nonlimiting list of preferredsubstituent groups includes hydroxyl, amino, alkoxy, carboxy, benzyl,phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl andalkynyl.

In certain embodiments, conjugate linkers comprise 1-10linker-nucleosides. In certain embodiments, such linker-nucleosides aremodified nucleosides. In certain embodiments such linker-nucleosidescomprise a modified sugar moiety. In certain embodiments,linker-nucleosides are unmodified. In certain embodiments,linker-nucleosides comprise an optionally protected heterocyclic baseselected from a purine, substituted purine, pyrimidine or substitutedpyrimidine. In certain embodiments, a cleavable moiety is a nucleosideselected from uracil, thymine, cytosine, 4-N-benzoylcytosine,5-methylcytosine, 4-N-benzoyl-5-methylcytosine, adenine,6-N-benzoyladenine, guanine and 2-N-isobutyrylguanine. It is typicallydesirable for linker-nucleosides to be cleaved from the compound afterit reaches a target tissue. Accordingly, linker-nucleosides aretypically linked to one another and to the remainder of the compoundthrough cleavable bonds. In certain embodiments, such cleavable bondsare phosphodiester bonds.

Herein, linker-nucleosides are not considered to be part of theoligonucleotide. Accordingly, in embodiments in which an compoundcomprises an oligonucleotide consisting of a specified number or rangeof linked nucleosides and/or a specified percent complementarity to areference nucleic acid and the compound also comprises a conjugate groupcomprising a conjugate linker comprising linker-nucleosides, thoselinker-nucleosides are not counted toward the length of theoligonucleotide and are not used in determining the percentcomplementarity of the oligonucleotide for the reference nucleic acid.For example, a compound may comprise (1) a modified oligonucleotideconsisting of 8-30 nucleosides and (2) a conjugate group comprising 1-10linker-nucleosides that are contiguous with the nucleosides of themodified oligonucleotide. The total number of contiguous linkednucleosides in such a compound is more than 30. Alternatively, acompound may comprise a modified oligonucleotide consisting of 8-30nucleosides and no conjugate group. The total number of contiguouslinked nucleosides in such a compound is no more than 30. Unlessotherwise indicated conjugate linkers comprise no more than 10linker-nucleosides. In certain embodiments, conjugate linkers compriseno more than 5 linker-nucleosides. In certain embodiments, conjugatelinkers comprise no more than 3 linker-nucleosides. In certainembodiments, conjugate linkers comprise no more than 2linker-nucleosides. In certain embodiments, conjugate linkers compriseno more than 1 linker-nucleoside.

In certain embodiments, it is desirable for a conjugate group to becleaved from the oligonucleotide. For example, in certain circumstancescompounds comprising a particular conjugate moiety are better taken upby a particular cell type, but once the compound has been taken up, itis desirable that the conjugate group be cleaved to release theunconjugated or parent oligonucleotide. Thus, certain conjugate linkersmay comprise one or more cleavable moieties. In certain embodiments, acleavable moiety is a cleavable bond. In certain embodiments, acleavable moiety is a group of atoms comprising at least one cleavablebond. In certain embodiments, a cleavable moiety comprises a group ofatoms having one, two, three, four, or more than four cleavable bonds.In certain embodiments, a cleavable moiety is selectively cleaved insidea cell or subcellular compartment, such as a lysosome. In certainembodiments, a cleavable moiety is selectively cleaved by endogenousenzymes, such as nucleases.

In certain embodiments, a cleavable bond is selected from among: anamide, an ester, an ether, one or both esters of a phosphodiester, aphosphate ester, a carbamate, or a disulfide. In certain embodiments, acleavable bond is one or both of the esters of a phosphodiester. Incertain embodiments, a cleavable moiety comprises a phosphate orphosphodiester. In certain embodiments, the cleavable moiety is aphosphate linkage between an oligonucleotide and a conjugate moiety orconjugate group.

In certain embodiments, a cleavable moiety comprises or consists of oneor more linker-nucleosides. In certain such embodiments, the one or morelinker-nucleosides are linked to one another and/or to the remainder ofthe compound through cleavable bonds. In certain embodiments, suchcleavable bonds are unmodified phosphodiester bonds. In certainembodiments, a cleavable moiety is 2′-deoxy nucleoside that is attachedto either the 3′ or 5′-terminal nucleoside of an oligonucleotide by aphosphate internucleoside linkage and covalently attached to theremainder of the conjugate linker or conjugate moiety by a phosphate orphosphorothioate linkage. In certain such embodiments, the cleavablemoiety is 2′-deoxyadenosine.

3. Certain Cell-Targeting Conjugate Moietiess

In certain embodiments, a conjugate group comprises a cell-targetingconjugate moiety. In certain embodiments, a conjugate group has thegeneral formula:

wherein n is from 1 to about 3, m is 0 when n is 1, m is 1 when n is 2or greater, j is 1 or 0, and k is 1 or 0.

In certain embodiments, n is 1, j is 1 and k is 0. In certainembodiments, n is 1, j is 0 and k is 1. In certain embodiments, n is 1,j is 1 and k is 1. In certain embodiments, n is 2, j is 1 and k is 0. Incertain embodiments, n is 2, j is 0 and k is 1. In certain embodiments,n is 2, j is 1 and k is 1. In certain embodiments, n is 3, j is 1 and kis 0. In certain embodiments, n is 3, j is 0 and k is 1. In certainembodiments, n is 3, j is 1 and k is 1.

In certain embodiments, conjugate groups comprise cell-targetingmoieties that have at least one tethered ligand. In certain embodiments,cell-targeting moieties comprise two tethered ligands covalentlyattached to a branching group. In certain embodiments, cell-targetingmoieties comprise three tethered ligands covalently attached to abranching group.

In certain embodiments, the cell-targeting moiety comprises a branchinggroup comprising one or more groups selected from alkyl, amino, oxo,amide, disulfide, polyethylene glycol, ether, thioether andhydroxylamino groups. In certain embodiments, the branching groupcomprises a branched aliphatic group comprising groups selected fromalkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether,thioether and hydroxylamino groups. In certain such embodiments, thebranched aliphatic group comprises groups selected from alkyl, amino,oxo, amide and ether groups. In certain such embodiments, the branchedaliphatic group comprises groups selected from alkyl, amino and ethergroups. In certain such embodiments, the branched aliphatic groupcomprises groups selected from alkyl and ether groups. In certainembodiments, the branching group comprises a mono or polycyclic ringsystem.

In certain embodiments, each tether of a cell-targeting moiety comprisesone or more groups selected from alkyl, substituted alkyl, ether,thioether, disulfide, amino, oxo, amide, phosphodiester, andpolyethylene glycol, in any combination. In certain embodiments, eachtether is a linear aliphatic group comprising one or more groupsselected from alkyl, ether, thioether, disulfide, amino, oxo, amide, andpolyethylene glycol, in any combination. In certain embodiments, eachtether is a linear aliphatic group comprising one or more groupsselected from alkyl, phosphodiester, ether, amino, oxo, and amide, inany combination. In certain embodiments, each tether is a linearaliphatic group comprising one or more groups selected from alkyl,ether, amino, oxo, and amid, in any combination. In certain embodiments,each tether is a linear aliphatic group comprising one or more groupsselected from alkyl, amino, and oxo, in any combination. In certainembodiments, each tether is a linear aliphatic group comprising one ormore groups selected from alkyl and oxo, in any combination. In certainembodiments, each tether is a linear aliphatic group comprising one ormore groups selected from alkyl and phosphodiester, in any combination.In certain embodiments, each tether comprises at least one phosphoruslinking group or neutral linking group. In certain embodiments, eachtether comprises a chain from about 6 to about 20 atoms in length. Incertain embodiments, each tether comprises a chain from about 10 toabout 18 atoms in length. In certain embodiments, each tether comprisesabout 10 atoms in chain length.

In certain embodiments, each ligand of a cell-targeting moiety has anaffinity for at least one type of receptor on a target cell. In certainembodiments, each ligand has an affinity for at least one type ofreceptor on the surface of a mammalian liver cell. In certainembodiments, each ligand has an affinity for the hepaticasialoglycoprotein receptor (ASGP-R). In certain embodiments, eachligand is a carbohydrate. In certain embodiments, each ligand is,independently selected from galactose, N-acetyl galactoseamine (GalNAc),mannose, glucose, glucoseamine and fucose. In certain embodiments, eachligand is N-acetyl galactoseamine (GalNAc). In certain embodiments, thecell-targeting moiety comprises 3 GalNAc ligands. In certainembodiments, the cell-targeting moiety comprises 2 GalNAc ligands. Incertain embodiments, the cell-targeting moiety comprises 1 GalNAcligand.

In certain embodiments, each ligand of a cell-targeting moiety is acarbohydrate, carbohydrate derivative, modified carbohydrate,polysaccharide, modified polysaccharide, or polysaccharide derivative.In certain such embodiments, the conjugate group comprises acarbohydrate cluster (see, e.g., Maier et al., “Synthesis of AntisenseOligonucleotides Conjugated to a Multivalent Carbohydrate Cluster forCellular Targeting,” Bioconjugate Chemistry, 2003, 14, 18-29 or Rensenet al., “Design and Synthesis of Novel N-Acetylgalactosamine-TerminatedGlycolipids for Targeting of Lipoproteins to the HepaticAsiaglycoprotein Receptor,” J. Med. Chem. 2004, 47, 5798-5808). Incertain such embodiments, each ligand is an amino sugar or a thio sugar.For example, amino sugars may be selected from any number of compoundsknown in the art, such as sialic acid, α-D-galactosamine, β-muramicacid, 2-deoxy-2-methylamino-L-glucopyranose,4,6-dideoxy-4-formamido-2,3-di-O-methyl-D-mannopyranose,2-deoxy-2-sulfoamino-D-glucopyranose and N-sulfo-D-glucosamine, andN-glycoloyl-α-neuraminic acid. For example, thio sugars may be selectedfrom 5-Thio-β-D-glucopyranose, methyl2,3,4-tri-O-acetyl-1-thio-6-O-trityl-α-D-glucopyranoside,galactopyranose, and ethyl3,4,6,7-tetra-O-acetyl-2-deoxy-1,5-dithio-α-D-gLuco-heptopyranoside.

In certain embodiments, conjugate groups comprise a cell-targetingmoiety having the formula:

In certain embodiments, conjugate groups comprise a cell-targetingmoiety having the formula:

In certain embodiments, conjugate groups comprise a cell-targetingmoiety having the formula:

In certain embodiments, conjugate groups comprise a cell-targetingmoiety having the formula:

In certain embodiments, conjugate groups comprise a cell-targetingmoiety having the formula:

In certain embodiments, compounds comprise a conjugate group describedherein as “LICA-1”. LICA-1 has the formula:

In certain embodiments, compounds described herein comprise LICA-1 and acleavable moiety within the conjugate linker have the formula:

wherein oligo is an oligonucleotide.

Representative United States patents, United States patent applicationpublications, international patent application publications, and otherpublications that teach the preparation of certain of the above notedconjugate groups, compounds comprising conjugate groups, tethers,conjugate linkers, branching groups, ligands, cleavable moieties as wellas other modifications include without limitation, U.S. Pat. Nos.5,994,517, 6,300,319, 6,660,720, 6,906,182, 7,262,177, 7,491,805,8,106,022, 7,723,509, US 2006/0148740, US 2011/0123520, WO 2013/033230and WO 2012/037254, Biessen et al., J. Med. Chem. 1995, 38, 1846-1852,Lee et al., Bioorganic & Medicinal Chemistry 2011, 19, 2494-2500, Rensenet al., J. Biol. Chem. 2001, 276, 37577-37584, Rensen et al., J. Med.Chem. 2004, 47, 5798-5808, Sliedregt et al., J. Med. Chem. 1999, 42,609-618, and Valentijn et al., Tetrahedron, 1997, 53, 759-770.

In certain embodiments, modified oligonucleotides comprise a gapmer orfully modified sugar motif and a conjugate group comprising at leastone, two, or three GalNAc ligands. In certain embodiments, compoundscomprise a conjugate group found in any of the following references:Lee, Carbohydr Res, 1978, 67, 509-514; Connolly et al., J Biol Chem,1982, 257, 939-945; Pavia et al., Int J Pep Protein Res, 1983, 22,539-548; Lee et al., Biochem, 1984, 23, 4255-4261; Lee et al.,Glycoconjugate J, 1987, 4, 317-328; Toyokuni et al., Tetrahedron Lett,1990, 31, 2673-2676; Biessen et al., J Med Chem, 1995, 38, 1538-1546;Valentijn et al., Tetrahedron, 1997, 53, 759-770; Kim et al.,Tetrahedron Lett, 1997, 38, 3487-3490; Lee et al., Bioconjug Chem, 1997,8, 762-765; Kato et al., Glycobiol, 2001, 11, 821-829; Rensen et al., JBiol Chem, 2001, 276, 37577-37584; Lee et al., Methods Enzymol, 2003,362, 38-43; Westerlind et al., Glycoconj J, 2004, 21, 227-241; Lee etal., Bioorg Med Chem Lett, 2006, 16(19), 5132-5135; Maierhofer et al.,Bioorg Med Chem, 2007, 15, 7661-7676; Khorev et al., Bioorg Med Chem,2008, 16, 5216-5231; Lee et al., Bioorg Med Chem, 2011, 19, 2494-2500;Kornilova et al., Analyt Biochem, 2012, 425, 43-46; Pujol et al., AngewChemie Int Ed Engl, 2012, 51, 7445-7448; Biessen et al., J Med Chem,1995, 38, 1846-1852; Sliedregt et al., J Med Chem, 1999, 42, 609-618;Rensen et al., J Med Chem, 2004, 47, 5798-5808; Rensen et al.,Arterioscler Thromb Vasc Biol, 2006, 26, 169-175; van Rossenberg et al.,Gene Ther, 2004, 11, 457-464; Sato et al., J Am Chem Soc, 2004, 126,14013-14022; Lee et al., J Org Chem, 2012, 77, 7564-7571; Biessen etal., FASEB J, 2000, 14, 1784-1792; Rajur et al., Bioconjug Chem, 1997,8, 935-940; Duff et al., Methods Enzymol, 2000, 313, 297-321; Maier etal., Bioconjug Chem, 2003, 14, 18-29; Jayaprakash et al., Org Lett,2010, 12, 5410-5413; Manoharan, Antisense Nucleic Acid Drug Dev, 2002,12, 103-128; Merwin et al., Bioconjug Chem, 1994, 5, 612-620; Tomiya etal., Bioorg Med Chem, 2013, 21, 5275-5281; International applicationsWO1998/013381; WO2011/038356; WO1997/046098; WO2008/098788;WO2004/101619; WO2012/037254; WO2011/120053; WO2011/100131;WO2011/163121; WO2012/177947; WO2013/033230; WO2013/075035;WO2012/083185; WO2012/083046; WO2009/082607; WO2009/134487;WO2010/144740; WO2010/148013; WO1997/020563; WO2010/088537;WO2002/043771; WO2010/129709; WO2012/068187; WO2009/126933;WO2004/024757; WO2010/054406; WO2012/089352; WO2012/089602;WO2013/166121; WO2013/165816; U.S. Pat. Nos. 4,751,219; 8,552,163;6,908,903; 7,262,177; 5,994,517; 6,300,319; 8,106,022; 7,491,805;7,491,805; 7,582,744; 8,137,695; 6,383,812; 6,525,031; 6,660,720;7,723,509; 8,541,548; 8,344,125; 8,313,772; 8,349,308; 8,450,467;8,501,930; 8,158,601; 7,262,177; 6,906,182; 6,620,916; 8,435,491;8,404,862; 7,851,615; Published U.S. Patent Application PublicationsUS2011/0097264; US2011/0097265; US2013/0004427; US2005/0164235;US2006/0148740; US2008/0281044; U52010/0240730; U52003/0119724;US2006/0183886; US2008/0206869; U52011/0269814; US2009/0286973;US2011/0207799; US2012/0136042; US2012/0165393; US2008/0281041;US2009/0203135; US2012/0035115; US2012/0095075; US2012/0101148;US2012/0128760; US2012/0157509; US2012/0230938; US2013/0109817;US2013/0121954; US2013/0178512; US2013/0236968; US2011/0123520;US2003/0077829; US2008/0108801; and US2009/0203132.

In certain embodiments, compounds are single-stranded. In certainembodiments, compounds are double-stranded.

Compositions and Methods for Formulating Pharmaceutical Compositions

Compounds described herein may be admixed with pharmaceuticallyacceptable active or inert substances for the preparation ofpharmaceutical compositions or formulations. Compositions and methodsfor the formulation of pharmaceutical compositions are dependent upon anumber of criteria, including, but not limited to, route ofadministration, extent of disease, or dose to be administered.

Certain embodiments provide pharmaceutical compositions comprising oneor more compounds or a salt thereof. In certain embodiments, thecompounds are antisense compounds or oligomeric compounds. In certainembodiments, the compounds comprise or consist of a modifiedoligonucleotide. In certain such embodiments, the pharmaceuticalcomposition comprises a suitable pharmaceutically acceptable diluent orcarrier. In certain embodiments, a pharmaceutical composition comprisesa sterile saline solution and one or more compound. In certainembodiments, such pharmaceutical composition consists of a sterilesaline solution and one or more compound. In certain embodiments, thesterile saline is pharmaceutical grade saline. In certain embodiments, apharmaceutical composition comprises one or more compound and sterilewater. In certain embodiments, a pharmaceutical composition consists ofone compound and sterile water. In certain embodiments, the sterilewater is pharmaceutical grade water. In certain embodiments, apharmaceutical composition comprises one or more compounds andphosphate-buffered saline (PBS). In certain embodiments, apharmaceutical composition consists of one or more compound and sterilePBS. In certain embodiments, the sterile PBS is pharmaceutical gradePBS. Compositions and methods for the formulation of pharmaceuticalcompositions are dependent upon a number of criteria, including, but notlimited to, route of administration, extent of disease, or dose to beadministered.

A compound described herein targeted to HSD17B13 nucleic acid can beutilized in pharmaceutical compositions by combining the compound with asuitable pharmaceutically acceptable diluent or carrier. In certainembodiments, a pharmaceutically acceptable diluent is water, such assterile water suitable for injection. Accordingly, in one embodiment,employed in the methods described herein is a pharmaceutical compositioncomprising a compound targeted to HSD17B13 nucleic acid and apharmaceutically acceptable diluent. In certain embodiments, thepharmaceutically acceptable diluent is water. In certain embodiments,the compound comprises or consists of a modified oligonucleotideprovided herein.

Pharmaceutical compositions comprising compounds provided hereinencompass any pharmaceutically acceptable salts, esters, or salts ofsuch esters, or any other oligonucleotide which, upon administration toan animal, including a human, is capable of providing (directly orindirectly) the biologically active metabolite or residue thereof. Incertain embodiments, the compounds are antisense compounds or oligomericcompounds. In certain embodiments, the compound comprises or consists ofa modified oligonucleotide. Accordingly, for example, the disclosure isalso drawn to pharmaceutically acceptable salts of compounds, prodrugs,pharmaceutically acceptable salts of such prodrugs, and otherbioequivalents. Suitable pharmaceutically acceptable salts include, butare not limited to, sodium and potassium salts.

A prodrug can include the incorporation of additional nucleosides at oneor both ends of a compound which are cleaved by endogenous nucleaseswithin the body, to form the active compound.

In certain embodiments, the compounds or compositions further comprise apharmaceutically acceptable carrier or diluent.

Examples

The Examples below describe the screening process to identify compoundstargeted to HSD17B13.

Non-Limiting Disclosure and Incorporation by Reference

Although the sequence listing accompanying this filing identifies eachsequence as either “RNA” or “DNA” as required, in reality, thosesequences may be modified with any combination of chemicalmodifications. One of skill in the art will readily appreciate that suchdesignation as “RNA” or “DNA” to describe modified oligonucleotides is,in certain instances, arbitrary. For example, an oligonucleotidecomprising a nucleoside comprising a 2′-OH sugar moiety and a thyminebase could be described as a DNA having a modified sugar (2′-OH for thenatural 2′-H of DNA) or as an RNA having a modified base (thymine(methylated uracil) for natural uracil of RNA).

Accordingly, nucleic acid sequences provided herein, including, but notlimited to, those in the sequence listing, are intended to encompassnucleic acids containing any combination of natural or modified RNAand/or DNA, including, but not limited to, such nucleic acids havingmodified nucleobases. By way of further example and without limitation,an oligonucleotide having the nucleobase sequence “ATCGATCG” encompassesany oligonucleotides having such nucleobase sequence, whether modifiedor unmodified, including, but not limited to, such compounds comprisingRNA bases, such as those having sequence “AUCGAUCG” and those havingsome DNA bases and some RNA bases such as “AUCGATCG” and compoundshaving other modified nucleobases, such as “ATmCGAUCG,” wherein mCindicates a cytosine base comprising a methyl group at the 5-position.

Certain compounds described herein (e.g. modified oligonucleotides) haveone or more asymmetric centers and thus give rise to enantiomers,diastereomers, and other stereoisomeric configurations that may bedefined, in terms of absolute stereochemistry, as (R) or (S), as α or β,such as for sugar anomers, or as (D) or (L), such as for amino acids,etc. Compounds provided herein that are drawn or described as havingcertain stereoisomeric configurations include only the indicatedcompounds. Compounds provided herein that are drawn or described withundefined stereochemistry include all such possible isomers, includingtheir stereorandom and optically pure forms. Likewise, all tautomericforms of the compounds provided herein are included unless otherwiseindicated. Unless otherwise indicated, oligomeric compounds and modifiedoligonucleotides described herein are intended to include correspondingsalt forms.

Compounds described herein include variations in which one or more atomsare replaced with a non-radioactive isotope or radioactive isotope ofthe indicated element. For example, compounds herein that comprisehydrogen atoms encompass all possible deuterium substitutions for eachof the ¹H hydrogen atoms. Isotopic substitutions encompassed by thecompounds herein include, but are not limited to: ²H or ³H in place of¹H, ¹³C or ¹⁴C in place of ¹²C, ¹⁵N in place of ¹⁴N, ¹⁷O or ¹⁸O in placeof ¹⁶O, and ³³S, ³⁴S, ³⁵S, or ³⁶S in place of ³²S.

While certain compounds, compositions and methods described herein havebeen described with specificity in accordance with certain embodiments,the following examples serve only to illustrate the compounds describedherein and are not intended to limit the same. Each of the referencesrecited in the present application is incorporated herein by referencein its entirety.

Example 1: Antisense Inhibition of Human HSD17B13 in HepaRG Cells by cEtGapmers

Modified oligonucleotides complementary to an HSD17B13 nucleic acid weresynthesized and tested for their effect on HSD17B13 RNA levels in vitro.The modified oligonucleotides were tested in a series of experimentsusing the same culture conditions. The results for each separateexperiment are presented in tables below.

The modified oligonucleotides were all 3-10-3 cEt gapmers (i.e. had acentral gap segment of ten 2′-deoxynucleosides flanked on each side bywing segments each comprising three cEt modified nucleosides). Theinternucleoside linkages throughout each modified oligonucleotide werephosphorothioate (P═S) linkages. All cytosine nucleobases throughouteach modified oligonucleotide were 5-methylcytosines.

“Start site” indicates the 5′-most nucleoside of the target sequence towhich the modified oligonucleotide is complementary. “Stop site”indicates the 3′-most nucleoside of the target sequence to which themodified oligonucleotide is complementary. As shown in the Tables below,the modified oligonucleotide are complementary to either the humanHSD17B13 mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No.NM_178135.4) or to the human HSD17B13 genomic sequence, designatedherein as SEQ ID NO: 2 (the complement of GENBANK Accession No.NC_000004.12 truncated from nucleotides 87301001 to 87326000) or toboth. ‘N/A’ indicates that the modified oligonucleotide is notcomplementary to that particular target sequence with 100%complementarity.

Cultured HepaRG cells at a density of 20,000 cells per well weretransfected using electroporation with 1,000 nM of modifiedoligonucleotide. After a treatment period of approximately 24 hours, RNAwas isolated from the cells and HSD17B13 RNA levels were measured byquantitative real-time RTPCR. Human primer probe set RTS43553 (forwardsequence AGACTACAGAAGTTTCTTCCTGAAC, designated herein as SEQ ID NO: 5;reverse sequence CATCTCTGGCTGGAGCTTATTT, designated herein as SEQ ID NO:6; probe sequence TTTGAAGCAGTGGTTGGCCACAAA, designated herein as SEQ IDNO: 7) was used to measure RNA levels. HSD17B13 RNA levels werenormalized to total RNA content, as measured by RIBOGREEN®. Results arepresented as percent inhibition of HSD17B13 relative to untreatedcontrol cells. As used herein, a value of ‘0’ indicates that treatmentwith the modified oligonucleotide did not inhibit HSD17B13 mRNA levels.An asterisk (*) indicates that the modified oligonucleotide iscomplementary to the target transcript within the amplicon region of theprimer probe set and so, the associated data is not reliable. In suchinstances, additional using alternate primer probe sets must beperformed to accurately assess the potency and efficacy of such modifiedoligonucleotides.

TABLE 1 Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmerstargeting SEQ ID NO: 1 and 2 SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO: NO: 2ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop Sequence (% IDNumber Site Site Site Site (5′ to 3′) Inhibition) NO 1245068 1 16 30953110 GGAGGAGGTACTGTCT 44 8 1245094 59 74 3153 3168 GATGTTCATGGCTTTG 81 91245120 111 126 3205 3220 ACTCCAAGTAGGAGTA 0 10 1245146 181 196 32753290 GCTCCAGTAATGAGAA 34 11 1245172 251 266 3345 3360 ATCCCACAGAACCAAT34 12 1245198 299 314 7588 7603 TAGTTTTCGGCACTCA 35 13 1245224 359 3747648 7663 AGAGCGATAGATCTCT 8 14 1245250 402 417 8796 8811CCACGATTGTTACATC 42 15 1245276 432 447 8826 8841 CGGCTGGATATACTGT 35 161245302 473 488 8867 8882 AAATGTCTTGGTAATC 30 17 1245328 515 530 1040110416 AAGTGCTTTTGTGATC 41 18 1245354 561 576 10447 10462CCACTGTGACGATGTG 0 19 1245380 614 629 N/A N/A GCTGGAACAATATGGG 36 201245406 670 685 12088 12103 CCCAAGGCCTGAAGTT 61 21 1245432 759 774 1564015655 ATACAGGCCATAATCT 0 22 1245458 790 805 15671 15686 ATCAGACTTCTTACGA45 23 1245484 842 857 15723 15738 ATTGATATACGATGGA 31 24 1245510* 907922 20722 20737 TTCTGCATACGATTTA 83 25 1245536* 973 988 20788 20803TCTGGCTGGAGCTTAT 85 26 1245562 1014 1029 20829 20844 CATTGATTCGAAACTA 4027 1245588 1088 1103 20903 20918 TTGACTGCTGCTAGTG 30 28 1245614 12601275 21075 21090 GGTAGCTTTTGTCCAC 66 29 1245640 1314 1329 21129 21144CAGTCTTAAACCTTCC 70 30 1245666 1341 1356 21156 21171 TGGCTACAGATTGGAA 5531 1245692 1385 1400 21200 21215 TTAGCTGTGCACTCAT 61 32 1245718 14231438 21238 21253 CCAGGTTGAGATAAAG 49 33 1245744 1499 1514 21314 21329AGAGTTGCACCGTTTT 76 34 1245770 1558 1573 21373 21388 CACTTTTGGTGGACTT 2135 1245796 1617 1632 21432 21447 CGGTCACCTTTCATAA 69 36 1245822 17101725 21525 21540 ATCTCTGGGACCAAGG 72 37 1245841 1765 1780 21580 21595GTACAGTTCCTTTTCC 55 38 1245848 1772 1787 21587 21602 ATAGCCAGTACAGTTC 6539 1245874 2177 2192 21992 22007 GGAGTCGGATTATTTT 41 40 1245900 22442259 22059 22074 GTCCATGCAAAAGCAT 62 41 1245926 N/A N/A 3405 3420AATACATATCTTACTC 37 42 1245952 N/A N/A 3552 3567 GTCATAAAAATCGCTG 72 431245978 N/A N/A 3948 3963 GAAAAGCCTGACTCAC 48 44 1246004 N/A N/A 45174532 CATCAAGCCCTTTTCA 23 45 1246030 N/A N/A 5078 5093 CTAAAGGAGATCTGAG47 46 1246056 N/A N/A 5222 5237 TAGCTTAAACTCCAAT 60 47 1246065 N/A N/A5659 5674 ATAAGTTACCAGAGCA 87 48 1246082 N/A N/A 5817 5832CTCAAAGTCAGTATCC 70 49 1246108 N/A N/A 5989 6004 GGCAAGGATACCTGAA 67 501246134 N/A N/A 6233 6248 CTCATTTATGTACCAA 87 51 1246160 N/A N/A 64746489 TATGTAATAGGCAGTA 62 52 1246186 N/A N/A 7482 7497 GACAATTAACATTCGG69 53 1246212 N/A N/A 7951 7966 CTAGGAAGTGATCCAT 66 54 1246238 N/A N/A8243 8258 CTAATAACTACATGAC 18 55 1246264 N/A N/A 8694 8709TCCAAAGATGAGAGTC 17 56 1246290 N/A N/A 9002 9017 GCAAAGATCTGGCCAG 22 571246316 N/A N/A 9348 9363 TCCAAAAGTGTCCTCG 31 58 1246342 N/A N/A 95189533 CTACACTAATATTGAG 20 59 1246368 N/A N/A 9715 9730 AGTGAACATACATTGT48 60 1246394 N/A N/A 9981 9996 ATTAAGACAGTTGAGT 34 61 1246420 N/A N/A10211 10226 ATTTATTGGTATGGTA 46 62 1246446 N/A N/A 10730 10745CTGTAATTGGCTCTTG 28 63 1246472 N/A N/A 11261 11276 TCTTATCTTGGGCACC 4464 1246498 N/A N/A 11742 11757 TCCATTGAATCTTCAA 57 65 1246524 N/A N/A11985 12000 GAAACCAATCCTCAGC 3 66 1246550 N/A N/A 12421 12436TGGTAACGGTGATCAA 74 67 1246576 N/A N/A 12624 12639 TTAAGCAGATGGCTTA 0 681246602 N/A N/A 12761 12776 ACAGAGAATTGTTTAG 39 69 1246628 N/A N/A 1360513620 AGACAATACAGGATAG 15 70 1246654 N/A N/A 13862 13877CCTTAGGAAAGCTCAT 29 71 1246680 N/A N/A 14041 14056 ATCAATGCCTTAGCCC 3872 1246706 N/A N/A 14199 14214 TATTATGTGATTGAGT 86 73 1246732 N/A N/A14399 14414 ATTCATAAACATAGGC 36 74 1246758 N/A N/A 14730 14745ACTCTAAATACCCTTG 16 75 1246784 N/A N/A 15316 15331 GGATTAATCATGGGAC 4476 1246810 N/A N/A 15405 15420 TCATAGCTCACTTAGT 0 77 1246836 N/A N/A15775 15790 TTTAGTATTTGGGTGT 21 78 1246862 N/A N/A 16407 16422CAATTGCTCTATAGAT 15 79 1246888 N/A N/A 17767 17782 AGCATATTCATTTGGC 6180 1246914 N/A N/A 18033 18048 AGTTTATATGGATTTG 67 81 1246940 N/A N/A18816 18831 CTAGTAATTGCATCTG 57 82 1246966 N/A N/A 19445 19460CTGGGATAGTGGAGGA 21 83 1246992 N/A N/A 19686 19701 GCTAAAAGCTCACCAA 2684 1247018 N/A N/A 19902 19917 GATACCCAGGTTGCTT 53 85 1247044 N/A N/A20186 20201 ATTAGAAGTCAGCCCA 42 86 1247070 N/A N/A 20401 20416GCTATAGTAATTGCTA 33 87

TABLE 2Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO: NO: 2 ID NO: HSD17B13 SEQ CompoundStart 1 Stop Start 2 Stop Sequence (% ID Number Site Site Site Site(5′ to 3′) Inhibition) NO 1245069 2 17 3096 3111 GGGAGGAGGTACTGTC 35 881245095 61 76 3155 3170 ATGATGTTCATGGCTT 72 89 1245121 112 127 3206 3221GACTCCAAGTAGGAGT 0 90 1245147 182 197 3276 3291 AGCTCCAGTAATGAGA 26 911245173 263 278 N/A N/A GCGCTTATTAATATCC 3 92 1245199 300 315 7589 7604CTAGTTTTCGGCACTC 33 93 1245225 360 375 7649 7664 GAGAGCGATAGATCTC 1 941245251 403 418 8797 8812 ACCACGATTGTTACAT 34 95 1245277 433 448 88278842 TCGGCTGGATATACTG 23 96 1245303 476 491 8870 8885 CTCAAATGTCTTGGTA29 97 1245329 516 531 10402 10417 GAAGTGCTTTTGTGAT 34 98 1245355 562 57710448 10463 GCCACTGTGACGATGT 9 99 1245381 615 630 N/A N/ATGCTGGAACAATATGG 36 100 1245407 671 686 12089 12104 TCCCAAGGCCTGAAGT 43101 1245433 760 775 15641 15656 AATACAGGCCATAATC 16 102 1245459 791 80615672 15687 TATCAGACTTCTTACG 59 103 1245485 843 858 15724 15739TATTGATATACGATGG 16 104 1245511* 908 923 20723 20738 ATTCTGCATACGATTT 89105 1245537* 974 989 20789 20804 CTCTGGCTGGAGCTTA 86 106 1245563 10151030 20830 20845 GCATTGATTCGAAACT 66 107 1245589 1089 1104 20904 20919TTTGACTGCTGCTAGT 21 108 1245615 1261 1276 21076 21091 AGGTAGCTTTTGTCCA56 109 1245641 1315 1330 21130 21145 ACAGTCTTAAACCTTC 76 110 12456671342 1357 21157 21172 ATGGCTACAGATTGGA 72 111 1245693 1386 1401 2120121216 CTTAGCTGTGCACTCA 60 112 1245719 1425 1440 21240 21255GTCCAGGTTGAGATAA 60 113 1245745 1500 1515 21315 21330 TAGAGTTGCACCGTTT58 114 1245771 1559 1574 21374 21389 CCACTTTTGGTGGACT 17 115 12457971618 1633 21433 21448 TCGGTCACCTTTCATA 64 116 1245823 1711 1726 2152621541 CATCTCTGGGACCAAG 51 117 1245841 1765 1780 21580 21595GTACAGTTCCTTTTCC 46 38 1245849 1773 1788 21588 21603 AATAGCCAGTACAGTT 46118 1245875 2178 2193 21993 22008 GGGAGTCGGATTATTT 33 119 1245901 22452260 22060 22075 AGTCCATGCAAAAGCA 77 120 1245927 N/A N/A 3433 3448AGTAGATGGTAAGTCA 90 121 1245953 N/A N/A 3553 3568 TGTCATAAAAATCGCT 57122 1245979 N/A N/A 3962 3977 TACTAATGTCCAAGGA 77 123 1246005 N/A N/A4529 4544 AAGGTTAGATTTCATC 80 124 1246031 N/A N/A 5079 5094CCTAAAGGAGATCTGA 48 125 1246057 N/A N/A 5225 5240 CTTTAGCTTAAACTCC 69126 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA 84 48 1246083 N/A N/A5833 5848 GATGTTAGGACCCAGT 64 127 1246109 N/A N/A 5990 6005AGGCAAGGATACCTGA 42 128 1246135 N/A N/A 6298 6313 GGAGATATAACATTAC 70129 1246161 N/A N/A 6475 6490 CTATGTAATAGGCAGT 73 130 1246187 N/A N/A7483 7498 AGACAATTAACATTCG 62 131 1246213 N/A N/A 7952 7967ACTAGGAAGTGATCCA 58 132 1246239 N/A N/A 8244 8259 CCTAATAACTACATGA 3 1331246265 N/A N/A 8695 8710 ATCCAAAGATGAGAGT 5 134 1246291 N/A N/A 90039018 GGCAAAGATCTGGCCA 10 135 1246317 N/A N/A 9349 9364 GTCCAAAAGTGTCCTC35 136 1246343 N/A N/A 9526 9541 CCTAGATTCTACACTA 14 137 1246369 N/A N/A9718 9733 GATAGTGAACATACAT 54 138 1246395 N/A N/A 9983 9998GTATTAAGACAGTTGA 45 139 1246421 N/A N/A 10212 10227 AATTTATTGGTATGGT 30140 1246447 N/A N/A 10831 10846 GTAAACGACTCTGTAA 8 141 1246473 N/A N/A11308 11323 GCACAAGCACACTGTA 7 142 1246499 N/A N/A 11758 11773CTACATGTAAGGTTTT 11 143 1246525 N/A N/A 12000 12015 TAGCTAAGGGAGAGTG 9144 1246551 N/A N/A 12429 12444 AGACAGGGTGGTAACG 51 145 1246577 N/A N/A12625 12640 GTTAAGCAGATGGCTT 41 146 1246603 N/A N/A 12765 12780CTCAACAGAGAATTGT 29 147 1246629 N/A N/A 13612 13627 GCTTTGAAGACAATAC 42148 1246655 N/A N/A 13863 13878 CCCTTAGGAAAGCTCA 37 149 1246681 N/A N/A14042 14057 TATCAATGCCTTAGCC 15 150 1246707 N/A N/A 14200 14215TTATTATGTGATTGAG 23 151 1246733 N/A N/A 14432 14447 ACTGAAGGCTGTGTAC 14152 1246759 N/A N/A 14731 14746 AACTCTAAATACCCTT 28 153 1246785 N/A N/A15317 15332 AGGATTAATCATGGGA 37 154 1246811 N/A N/A 15407 15422TTTCATAGCTCACTTA 16 155 1246837 N/A N/A 15787 15802 CTCTATTGGTGTTTTA 32156 1246863 N/A N/A 16416 16431 AATACTCCCCAATTGC 0 157 1246889 N/A N/A17780 17795 AGAAGATATTATCAGC 64 158 1246915 N/A N/A 18087 18102CACCAATGCAGTTTGT 42 159 1246941 N/A N/A 18817 18832 GCTAGTAATTGCATCT 47160 1246967 N/A N/A 19474 19489 GCTATAACTGGAAGGA 58 161 1246993 N/A N/A19687 19702 TGCTAAAAGCTCACCA 49 162 1247019 N/A N/A 19906 19921TTAAGATACCCAGGTT 37 163 1247045 N/A N/A 20187 20202 TATTAGAAGTCAGCCC 27164 1247071 N/A N/A 20402 20417 GGCTATAGTAATTGCT 13 165

TABLE 3Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1 and 2SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO: NO: 2 ID NO: HSD17B13 SEQ CompoundStart 1 Stop Start 2 Stop Sequence (% ID Number Site Site Site Site(5′ to 3′) Inhibition) NO 1245070 5 20 3099 3114 CTAGGGAGGAGGTACT 29 1661245096 62 77 3156 3171 GATGATGTTCATGGCT 86 167 1245122 113 128 32073222 CGACTCCAAGTAGGAG 10 168 1245148 200 215 3294 3309 CCTGCCTATTCCATGC24 169 1245174 264 279 N/A N/A CGCGCTTATTAATATC 6 170 1245200 301 3167590 7605 CCTAGTTTTCGGCACT 62 171 1245226 361 376 7650 7665AGAGAGCGATAGATCT 15 172 1245252 404 419 8798 8813 CACCACGATTGTTACA 36173 1245278 434 449 8828 8843 ATCGGCTGGATATACT 10 174 1245304 477 4928871 8886 CCTCAAATGTCTTGGT 6 175 1245330 524 539 10410 10425CGATGGAAGAAGTGCT 3 176 1245356 563 578 10449 10464 AGCCACTGTGACGATG 10177 1245382 616 631 N/A N/A TTGCTGGAACAATATG 20 178 1245408 688 70312106 12121 GTTTTGATACCAGTTT 67 179 1245434 761 776 15642 15657CAATACAGGCCATAAT 0 180 1245460 792 807 15673 15688 CTATCAGACTTCTTAC 39181 1245486 844 859 15725 15740 ATATTGATATACGATG 0 182 1245512* 909 92420724 20739 TATTCTGCATACGATT 81 183 1245538* 975 990 20790 20805TCTCTGGCTGGAGCTT 90 184 1245564 1016 1031 20831 20846 AGCATTGATTCGAAAC70 185 1245590 1090 1105 20905 20920 GTTTGACTGCTGCTAG 58 186 12456161262 1277 21077 21092 GAGGTAGCTTTTGTCC 59 187 1245642 1316 1331 2113121146 AACAGTCTTAAACCTT 82 188 1245668 1343 1358 21158 21173CATGGCTACAGATTGG 54 189 1245694 1387 1402 21202 21217 TCTTAGCTGTGCACTC69 190 1245720 1426 1441 21241 21256 TGTCCAGGTTGAGATA 48 191 12457461501 1516 21316 21331 ATAGAGTTGCACCGTT 57 192 1245772 1560 1575 2137521390 TCCACTTTTGGTGGAC 16 193 1245798 1619 1634 21434 21449GTCGGTCACCTTTCAT 85 194 1245824 1712 1727 21527 21542 ACATCTCTGGGACCAA78 195 1245841 1765 1780 21580 21595 GTACAGTTCCTTTTCC 64 38 1245850 17741789 21589 21604 TAATAGCCAGTACAGT 64 196 1245876 2179 2194 21994 22009TGGGAGTCGGATTATT 44 197 1245902 2246 2261 22061 22076 TAGTCCATGCAAAAGC66 198 1245928 N/A N/A 3434 3449 AAGTAGATGGTAAGTC 85 199 1245954 N/A N/A3554 3569 ATGTCATAAAAATCGC 53 200 1245980 N/A N/A 3963 3978ATACTAATGTCCAAGG 89 201 1246006 N/A N/A 4535 4550 GATTTGAAGGTTAGAT 47202 1246032 N/A N/A 5080 5095 GCCTAAAGGAGATCTG 67 203 1246058 N/A N/A5239 5254 TAGCAAAACACTTGCT 21 204 1246065 N/A N/A 5659 5674ATAAGTTACCAGAGCA 87 48 1246084 N/A N/A 5834 5849 GGATGTTAGGACCCAG 81 2051246110 N/A N/A 6035 6050 ATACTTTTCCGTCTCA 90 206 1246136 N/A N/A 63036318 CTCTAGGAGATATAAC 49 207 1246162 N/A N/A 6476 6491 ACTATGTAATAGGCAG85 208 1246188 N/A N/A 7681 7696 AAATTTGTGAACCTGC 26 209 1246214 N/A N/A7953 7968 AACTAGGAAGTGATCC 58 210 1246240 N/A N/A 8245 8260ACCTAATAACTACATG 0 211 1246266 N/A N/A 8703 8718 CCAATATAATCCAAAG 28 2121246292 N/A N/A 9006 9021 TAAGGCAAAGATCTGG 46 213 1246318 N/A N/A 93509365 CGTCCAAAAGTGTCCT 53 214 1246344 N/A N/A 9527 9542 CCCTAGATTCTACACT22 215 1246370 N/A N/A 9719 9734 GGATAGTGAACATACA 62 216 1246396 N/A N/A9984 9999 TGTATTAAGACAGTTG 34 217 1246422 N/A N/A 10335 10350CCAAATCAGGTAGTTT 13 218 1246448 N/A N/A 10832 10847 AGTAAACGACTCTGTA 33219 1246474 N/A N/A 11385 11400 TTTTAGTCAGGTAGAG 3 220 1246500 N/A N/A11761 11776 ATCCTACATGTAAGGT 24 221 1246526 N/A N/A 12002 12017GTTAGCTAAGGGAGAG 18 222 1246552 N/A N/A 12433 12448 TTAAAGACAGGGTGGT 21223 1246578 N/A N/A 12626 12641 TGTTAAGCAGATGGCT 39 224 1246604 N/A N/A12777 12792 AATGAGGCGGCACTCA 20 225 1246630 N/A N/A 13639 13654TGACAATGTGCAGCTC 64 226 1246656 N/A N/A 13864 13879 ACCCTTAGGAAAGCTC 52227 1246682 N/A N/A 14043 14058 ATATCAATGCCTTAGC 32 228 1246708 N/A N/A14202 14217 GATTATTATGTGATTG 39 229 1246734 N/A N/A 14435 14450TATACTGAAGGCTGTG 44 230 1246760 N/A N/A 14800 14815 GAATTGCTCACCCTTT 24231 1246786 N/A N/A 15318 15333 TAGGATTAATCATGGG 47 232 1246812 N/A N/A15418 15433 CAGTAGGTGTGTTTCA 47 233 1246838 N/A N/A 15793 15808AAAAAGCTCTATTGGT 0 234 1246864 N/A N/A 16424 16439 GATATGTCAATACTCC 59235 1246890 N/A N/A 17857 17872 CATTTGAAGTCTATAC 21 236 1246916 N/A N/A18091 18106 GATACACCAATGCAGT 73 237 1246942 N/A N/A 18818 18833TGCTAGTAATTGCATC 17 238 1246968 N/A N/A 19475 19490 GGCTATAACTGGAAGG 52239 1246994 N/A N/A 19688 19703 ATGCTAAAAGCTCACC 50 240 1247020 N/A N/A19907 19922 CTTAAGATACCCAGGT 36 241 1247046 N/A N/A 20188 20203TTATTAGAAGTCAGCC 36 242 1247072 N/A N/A 20403 20418 TGGCTATAGTAATTGC 34243

TABLE 4Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1, and 2SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO: NO: 2 ID NO: HSD17B13 SEQ CompoundStart 1 Stop Start 2 Stop Sequence (% ID Number Site Site Site Site(5′ to 3′) Inhibition) NO 1245071 6 21 3100 3115 CCTAGGGAGGAGGTAC 34 2441245097 63 78 3157 3172 GGATGATGTTCATGGC 82 245 1245123 114 129 32083223 ACGACTCCAAGTAGGA 24 246 1245149 202 217 3296 3311 TGCCTGCCTATTCCAT40 247 1245175 265 280 N/A N/A CCGCGCTTATTAATAT 21 248 1245201 302 3177591 7606 GCCTAGTTTTCGGCAC 12 249 1245227 362 377 7651 7666TAGAGAGCGATAGATC 22 250 1245253 405 420 8799 8814 TCACCACGATTGTTAC 34251 1245279 435 450 8829 8844 GATCGGCTGGATATAC 7 252 1245305 478 4938872 8887 ACCTCAAATGTCTTGG 17 253 1245331 525 540 10411 10426TCGATGGAAGAAGTGC 34 254 1245357 566 581 10452 10467 TGAAGCCACTGTGACG 49255 1245383 623 638 12041 12056 GGCAAATTTGCTGGAA 54 256 1245409 689 70412107 12122 GGTTTTGATACCAGTT 58 257 1245435 762 777 15643 15658CCAATACAGGCCATAA 38 258 1245461 793 808 15674 15689 TCTATCAGACTTCTTA 49259 1245487 845 860 15726 15741 GATATTGATATACGAT 2 260 1245513* 910 92520725 20740 ATATTCTGCATACGAT 36 261 1245539* 977 992 20792 20807CATCTCTGGCTGGAGC 79 262 1245565 1017 1032 20832 20847 CAGCATTGATTCGAAA69 263 1245591 1091 1106 20906 20921 CGTTTGACTGCTGCTA 58 264 12456171263 1278 21078 21093 GGAGGTAGCTTTTGTC 43 265 1245643 1317 1332 2113221147 GAACAGTCTTAAACCT 64 266 1245669 1344 1359 21159 21174GCATGGCTACAGATTG 56 267 1245695 1388 1403 21203 21218 CTCTTAGCTGTGCACT53 268 1245721 1427 1442 21242 21257 ATGTCCAGGTTGAGAT 55 269 12457471502 1517 21317 21332 AATAGAGTTGCACCGT 48 270 1245773 1561 1576 2137621391 GTCCACTTTTGGTGGA 14 271 1245799 1620 1635 21435 21450AGTCGGTCACCTTTCA 66 272 1245825 1713 1728 21528 21543 AACATCTCTGGGACCA74 273 1245851 1775 1790 21590 21605 GTAATAGCCAGTACAG 77 274 12458772180 2195 21995 22010 GTGGGAGTCGGATTAT 37 275 1245903 2251 2266 2206622081 GAGGATAGTCCATGCA 59 276 1245929 N/A N/A 3437 3452 GATAAGTAGATGGTAA59 277 1245955 N/A N/A 3573 3588 TTCTATCAACCTGCAC 62 278 1245981 N/A N/A3964 3979 AATACTAATGTCCAAG 65 279 1246007 N/A N/A 4572 4587ATATAGCCCTTTCCCC 26 280 1246033 N/A N/A 5081 5096 CGCCTAAAGGAGATCT 59281 1246059 N/A N/A 5241 5256 GTTAGCAAAACACTTG 71 282 1246085 N/A N/A5840 5855 AAACATGGATGTTAGG 56 283 1246111 N/A N/A 6036 6051TATACTTTTCCGTCTC 71 284 1246137 N/A N/A 6305 6320 TACTCTAGGAGATATA 33285 1246163 N/A N/A 6478 6493 CAACTATGTAATAGGC 79 286 1246189 N/A N/A7684 7699 AAGAAATTTGTGAACC 21 287 1246215 N/A N/A 7973 7988AGTTAATAGGACTAAA 13 288 1246241 N/A N/A 8246 8261 AACCTAATAACTACAT 0 2891246267 N/A N/A 8705 8720 GACCAATATAATCCAA 34 290 1246293 N/A N/A 90099024 GATTAAGGCAAAGATC 25 291 1246319 N/A N/A 9373 9388 CTAGAACACTTGCCTC25 292 1246345 N/A N/A 9540 9555 GAATCCAGATCTGCCC 29 293 1246371 N/A N/A9721 9736 GAGGATAGTGAACATA 50 294 1246397 N/A N/A 9985 10000CTGTATTAAGACAGTT 41 295 1246423 N/A N/A 10336 10351 TCCAAATCAGGTAGTT 22296 1246449 N/A N/A 10833 10848 GAGTAAACGACTCTGT 43 297 1246475 N/A N/A11386 11401 CTTTTAGTCAGGTAGA 33 298 1246501 N/A N/A 11780 11795GCTTAATGTTCAGTTT 50 299 1246527 N/A N/A 12009 12024 AAGCATTGTTAGCTAA 11300 1246553 N/A N/A 12465 12480 ATTTATTTGCTGGTCC 47 301 1246579 N/A N/A12647 12662 TATACTAGGATTAGAA 2 302 1246605 N/A N/A 12778 12793AAATGAGGCGGCACTC 20 303 1246631 N/A N/A 13704 13719 AATGTAAGAAGCCACG 26304 1246657 N/A N/A 13881 13896 CCCAAGAGTGGCAGGA 29 305 1246683 N/A N/A14044 14059 CATATCAATGCCTTAG 29 306 1246709 N/A N/A 14205 14220GCAGATTATTATGTGA 59 307 1246735 N/A N/A 14436 14451 TTATACTGAAGGCTGT 23308 1246761 N/A N/A 14916 14931 ATACATTAGCAAGCTA 69 309 1246787 N/A N/A15319 15334 CTAGGATTAATCATGG 65 310 1246813 N/A N/A 15420 15435TCCAGTAGGTGTGTTT 47 311 1246839 N/A N/A 16116 16131 CTCTATTGGGCCAGGC 46312 1246865 N/A N/A 16461 16476 GATATTATGTTCTTGG 59 313 1246891 N/A N/A17909 17924 GGAAATTGTTGCTGTT 46 314 1246917 N/A N/A 18097 18112GAAATTGATACACCAA 67 315 1246943 N/A N/A 18819 18834 ATGCTAGTAATTGCAT 16316 1246969 N/A N/A 19484 19499 AGAATTAAGGGCTATA 45 317 1246995 N/A N/A19689 19704 GATGCTAAAAGCTCAC 46 318 1247021 N/A N/A 19908 19923TCTTAAGATACCCAGG 58 319 1247047 N/A N/A 20189 20204 GTTATTAGAAGTCAGC 56320 1247073 N/A N/A 20415 20430 AATTATGCCTTGTGGC 19 321

TABLE 5Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1, and 2SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO: NO: 2 ID NO: HSD17B13 SEQ CompoundStart 1 Stop Start 2 Stop Sequence (% ID Number Site Site Site Site(5′ to 3′) Inhibition) NO 1245072 7 22 3101 3116 TCCTAGGGAGGAGGTA 33 3221245098 64 79 3158 3173 AGGATGATGTTCATGG 88 323 1245124 115 130 32093224 AACGACTCCAAGTAGG 27 324 1245150 205 220 3299 3314 GTCTGCCTGCCTATTC53 325 1245176 266 281 N/A N/A ACCGCGCTTATTAATA 4 326 1245202 303 3187592 7607 CGCCTAGTTTTCGGCA 23 327 1245228 363 378 7652 7667TTAGAGAGCGATAGAT 23 328 1245254 406 421 8800 8815 TTCACCACGATTGTTA 40329 1245280 436 451 8830 8845 AGATCGGCTGGATATA 27 330 1245306 479 4948873 8888 GACCTCAAATGTCTTG 12 331 1245332 526 541 10412 10427ATCGATGGAAGAAGTG 39 332 1245358 573 588 10459 10474 CGCACACTGAAGCCAC 56333 1245384 624 639 12042 12057 CGGCAAATTTGCTGGA 29 334 1245410 690 70512108 12123 AGGTTTTGATACCAGT 60 335 1245436 763 778 15644 15659TCCAATACAGGCCATA 62 336 1245462 795 810 15676 15691 CATCTATCAGACTTCT 38337 1245488 846 861 15727 15742 AGATATTGATATACGA 20 338 1245514* 911 92620726 20741 AATATTCTGCATACGA 70 339 1245540* 978 993 20793 20808ACATCTCTGGCTGGAG 85 340 1245566 1018 1033 20833 20848 GCAGCATTGATTCGAA63 341 1245592 1105 1120 20920 20935 TAATTAATCTTGTTCG 63 342 12456181264 1279 21079 21094 GGGAGGTAGCTTTTGT 10 343 1245644 1318 1333 2113321148 TGAACAGTCTTAAACC 56 344 1245670 1345 1360 21160 21175GGCATGGCTACAGATT 69 345 1245696 1389 1404 21204 21219 TCTCTTAGCTGTGCAC79 346 1245722 1428 1443 21243 21258 TATGTCCAGGTTGAGA 64 347 12457481503 1518 21318 21333 GAATAGAGTTGCACCG 55 348 1245774 1562 1577 2137721392 GGTCCACTTTTGGTGG 13 349 1245800 1621 1636 21436 21451GAGTCGGTCACCTTTC 82 350 1245826 1715 1730 21530 21545 TAAACATCTCTGGGAC51 351 1245841 1765 1780 21580 21595 GTACAGTTCCTTTTCC 58 38 1245852 17761791 21591 21606 TGTAATAGCCAGTACA 46 352 1245878 2181 2196 21996 22011AGTGGGAGTCGGATTA 50 353 1245904 2252 2267 22067 22082 AGAGGATAGTCCATGC74 354 1245930 N/A N/A 3439 3454 AAGATAAGTAGATGGT 79 355 1245956 N/A N/A3602 3617 AGCTTGGAAGGAGACT 69 356 1245982 N/A N/A 3999 4014GTTAATGTAGTGTTTA 77 357 1246008 N/A N/A 4573 4588 AATATAGCCCTTTCCC 44358 1246034 N/A N/A 5082 5097 TCGCCTAAAGGAGATC 70 359 1246060 N/A N/A5267 5282 TGCAAAATGTGATGCC 69 360 1246065 N/A N/A 5659 5674ATAAGTTACCAGAGCA 90 48 1246086 N/A N/A 5841 5856 CAAACATGGATGTTAG 49 3611246112 N/A N/A 6037 6052 TTATACTTTTCCGTCT 61 362 1246138 N/A N/A 63236338 ATAGGGAGACCATGCT 64 363 1246164 N/A N/A 6567 6582 AAAACATTGCTCTTCG59 364 1246190 N/A N/A 7751 7766 TAAATCAGGCAGTCAT 35 365 1246216 N/A N/A7974 7989 AAGTTAATAGGACTAA 17 366 1246242 N/A N/A 8248 8263ATAACCTAATAACTAC 26 367 1246268 N/A N/A 8714 8729 AAGTTTTGGGACCAAT 11368 1246294 N/A N/A 9012 9027 CTTGATTAAGGCAAAG 38 369 1246320 N/A N/A9375 9390 ATCTAGAACACTTGCC 27 370 1246346 N/A N/A 9588 9603CTGGTAAAGGTAAGGG 58 371 1246372 N/A N/A 9722 9737 AGAGGATAGTGAACAT 59372 1246398 N/A N/A 9986 10001 ACTGTATTAAGACAGT 20 373 1246424 N/A N/A10337 10352 TTCCAAATCAGGTAGT 12 374 1246450 N/A N/A 10834 10849TGAGTAAACGACTCTG 23 375 1246476 N/A N/A 11387 11402 ACTTTTAGTCAGGTAG 26376 1246502 N/A N/A 11781 11796 GGCTTAATGTTCAGTT 54 377 1246528 N/A N/A12011 12026 TTAAGCATTGTTAGCT 16 378 1246554 N/A N/A 12466 12481AATTTATTTGCTGGTC 27 379 1246580 N/A N/A 12648 12663 ATATACTAGGATTAGA 33380 1246606 N/A N/A 12779 12794 CAAATGAGGCGGCACT 32 381 1246632 N/A N/A13707 13722 GCAAATGTAAGAAGCC 4 382 1246658 N/A N/A 13894 13909CTATCATGCCTTCCCC 1 383 1246684 N/A N/A 14046 14061 TACATATCAATGCCTT 38384 1246710 N/A N/A 14206 14221 TGCAGATTATTATGTG 38 385 1246736 N/A N/A14437 14452 CTTATACTGAAGGCTG 48 386 1246762 N/A N/A 14934 14949CATTATAAGCTAACTA 39 387 1246788 N/A N/A 15321 15336 GGCTAGGATTAATCAT 44388 1246814 N/A N/A 15421 15436 ATCCAGTAGGTGTGTT 41 389 1246840 N/A N/A16123 16138 ATAATAGCTCTATTGG 46 390 1246866 N/A N/A 16533 16548CAAGACTTAAACACCA 55 391 1246892 N/A N/A 17910 17925 GGGAAATTGTTGCTGT 42392 1246918 N/A N/A 18099 18114 CTGAAATTGATACACC 67 393 1246944 N/A N/A18827 18842 AAACCTTCATGCTAGT 27 394 1246970 N/A N/A 19485 19500TAGAATTAAGGGCTAT 31 395 1246996 N/A N/A 19699 19714 GATTAATCTTGATGCT 26396 1247022 N/A N/A 19909 19924 ATCTTAAGATACCCAG 70 397 1247048 N/A N/A20192 20207 GCAGTTATTAGAAGTC 76 398 1247074 N/A N/A 20419 20434GTAAAATTATGCCTTG 50 399

TABLE 6Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1, and 2SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO: NO: 2 ID NO: HSD17B13 SEQ CompoundStart 1 Stop Start 2 Stop Sequence (% ID Number Site Site Site Site(5′ to 3′) Inhibition) NO 1245073 8 23 3102 3117 GTCCTAGGGAGGAGGT 36 4001245099 65 80 3159 3174 TAGGATGATGTTCATG 72 401 1245125 116 131 32103225 CAACGACTCCAAGTAG 0 402 1245151 206 221 3300 3315 AGTCTGCCTGCCTATT47 403 1245177 267 282 N/A N/A CACCGCGCTTATTAAT 7 404 1245203 304 3197593 7608 ACGCCTAGTTTTCGGC 7 405 1245229 364 379 7653 7668TTTAGAGAGCGATAGA 13 406 1245255 407 422 8801 8816 ATTCACCACGATTGTT 0 4071245281 437 452 8831 8846 AAGATCGGCTGGATAT 1 408 1245307 481 496 88758890 TTGACCTCAAATGTCT 0 409 1245333 527 542 10413 10428 CATCGATGGAAGAAGT16 410 1245359 574 589 10460 10475 CCGCACACTGAAGCCA 34 411 1245385 625640 12043 12058 GCGGCAAATTTGCTGG 0 412 1245411 691 706 12109 12124GAGGTTTTGATACCAG 59 413 1245437 764 779 15645 15660 CTCCAATACAGGCCAT 20414 1245463 796 811 15677 15692 CCATCTATCAGACTTC 78 415 1245489 847 86215728 15743 AAGATATTGATATACG 45 416 1245515* 912 927 20727 20742GAATATTCTGCATACG 68 417 1245541* 979 994 20794 20809 TACATCTCTGGCTGGA 86418 1245567 1019 1034 20834 20849 TGCAGCATTGATTCGA 47 419 1245593 11061121 20921 20936 GTAATTAATCTTGTTC 52 420 1245619 1265 1280 21080 21095AGGGAGGTAGCTTTTG 46 421 1245645 1319 1334 21134 21149 TTGAACAGTCTTAAAC33 422 1245671 1346 1361 21161 21176 TGGCATGGCTACAGAT 57 423 12456971390 1405 21205 21220 ATCTCTTAGCTGTGCA 63 424 1245723 1429 1444 2124421259 ATATGTCCAGGTTGAG 61 425 1245749 1504 1519 21319 21334AGAATAGAGTTGCACC 70 426 1245775 1563 1578 21378 21393 GGGTCCACTTTTGGTG13 427 1245801 1622 1637 21437 21452 AGAGTCGGTCACCTTT 71 428 12458271718 1733 21533 21548 GTCTAAACATCTCTGG 58 429 1245841 1765 1780 2158021595 GTACAGTTCCTTTTCC 57 38 1245853 1777 1792 21592 21607ATGTAATAGCCAGTAC 52 430 1245879 2182 2197 21997 22012 TAGTGGGAGTCGGATT54 431 1245905 2253 2268 22068 22083 AAGAGGATAGTCCATG 65 432 1245931 N/AN/A 3474 3489 AGGGAATTTATCAAAC 47 433 1245957 N/A N/A 3610 3625CATTTAGCAGCTTGGA 88 434 1245983 N/A N/A 4002 4017 GTTGTTAATGTAGTGT 77435 1246009 N/A N/A 4641 4656 ATACGACTTCCTTCTA 44 436 1246035 N/A N/A5104 5119 GAAAACTCAGCCAGCA 78 437 1246061 N/A N/A 5278 5293AGCTAGACAATTGCAA 30 438 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA 87 481246087 N/A N/A 5842 5857 CCAAACATGGATGTTA 43 439 1246113 N/A N/A 60386053 ATTATACTTTTCCGTC 75 440 1246139 N/A N/A 6327 6342 TTTCATAGGGAGACCA71 441 1246165 N/A N/A 6607 6622 CTAAAGCAGGCTACTT 32 442 1246191 N/A N/A7752 7767 TTAAATCAGGCAGTCA 45 443 1246217 N/A N/A 7975 7990AAAGTTAATAGGACTA 12 444 1246243 N/A N/A 8249 8264 CATAACCTAATAACTA 10445 1246269 N/A N/A 8717 8732 TCAAAGTTTTGGGACC 42 446 1246295 N/A N/A9080 9095 TCCACTTGAATTCTGT 32 447 1246321 N/A N/A 9376 9391GATCTAGAACACTTGC 27 448 1246347 N/A N/A 9589 9604 GCTGGTAAAGGTAAGG 65449 1246373 N/A N/A 9751 9766 CTCCAAATTCCCAACC 31 450 1246399 N/A N/A9998 10013 AAATCTTGTGTAACTG 41 451 1246425 N/A N/A 10359 10374GACAATGACATAGACG 0 452 1246451 N/A N/A 10835 10850 CTGAGTAAACGACTCT 33453 1246477 N/A N/A 11389 11404 CAACTTTTAGTCAGGT 66 454 1246503 N/A N/A11782 11797 TGGCTTAATGTTCAGT 50 455 1246529 N/A N/A 12012 12027ATTAAGCATTGTTAGC 0 456 1246555 N/A N/A 12467 12482 CAATTTATTTGCTGGT 31457 1246581 N/A N/A 12649 12664 TATATACTAGGATTAG 10 458 1246607 N/A N/A12781 12796 CTCAAATGAGGCGGCA 56 459 1246633 N/A N/A 13711 13726CGTAGCAAATGTAAGA 0 460 1246659 N/A N/A 13896 13911 ATCTATCATGCCTTCC 6461 1246685 N/A N/A 14047 14062 TTACATATCAATGCCT 12 462 1246711 N/A N/A14243 14258 GTTAAAACTTCATTCC 5 463 1246737 N/A N/A 14438 14453CCTTATACTGAAGGCT 41 464 1246763 N/A N/A 14935 14950 TCATTATAAGCTAACT 0465 1246789 N/A N/A 15328 15343 GAGGAATGGCTAGGAT 47 466 1246815 N/A N/A15424 15439 CATATCCAGTAGGTGT 37 467 1246841 N/A N/A 16128 16143CCATAATAATAGCTCT 48 468 1246867 N/A N/A 16755 16770 AAAGTTAGTTGGGCGA 26469 1246893 N/A N/A 17911 17926 TGGGAAATTGTTGCTG 38 470 1246919 N/A N/A18100 18115 ACTGAAATTGATACAC 49 471 1246945 N/A N/A 18828 18843GAAACCTTCATGCTAG 31 472 1246971 N/A N/A 19486 19501 CTAGAATTAAGGGCTA 42473 1246997 N/A N/A 19700 19715 TGATTAATCTTGATGC 15 474 1247023 N/A N/A19910 19925 CATCTTAAGATACCCA 76 475 1247049 N/A N/A 20248 20263CCTAAACAAACACTAT 8 476 1247075 N/A N/A 20422 20437 ACAGTAAAATTATGCC 73477

TABLE 7 Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmerstargeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO: NO: 2ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop (% ID Number SiteSite Site Site Sequence (5′ to 3′) Inhibition) NO 1245074 10 25 31043119 TAGTCCTAGGGAGGAG 68 478 1245100 66 81 3160 3175 CTAGGATGATGTTCAT 47479 1245126 117 132 3211 3226 CCAACGACTCCAAGTA 20 480 1245152 207 2223301 3316 TAGTCTGCCTGCCTAT 44 481 1245178 268 283 N/A N/AACACCGCGCTTATTAA 7 482 1245204 316 331 7605 7620 GCATGCGCAGTGACGC 36 4831245230 365 380 7654 7669 ATTTAGAGAGCGATAG 14 484 1245256 408 423 88028817 TATTCACCACGATTGT 2 485 1245282 438 453 8832 8847 GAAGATCGGCTGGATA16 486 1245308 482 497 8876 8891 GTTGACCTCAAATGTC 0 487 1245334 528 54310414 10429 TCATCGATGGAAGAAG 24 488 1245360 575 590 10461 10476GCCGCACACTGAAGCC 25 489 1245386 626 641 12044 12059 AGCGGCAAATTTGCTG 5490 1245412 692 707 12110 12125 TGAGGTTTTGATACCA 63 491 1245438 765 78015646 15661 TCTCCAATACAGGCCA 21 492 1245464 797 812 15678 15693TCCATCTATCAGACTT 42 493 1245490* 858 873 15739 15754 GTAGTCTCAGAAAGAT 45494 1245516* 926 941 20741 20756 CACTGCTTCAAATTGA 64 495 1245542* 980995 20795 20810 ATACATCTCTGGCTGG 88 496 1245568 1020 1035 20835 20850TTGCAGCATTGATTCG 59 497 1245594 1107 1122 20922 20937 GGTAATTAATCTTGTT58 498 1245620 1266 1281 21081 21096 TAGGGAGGTAGCTTTT 46 499 12456461320 1335 21135 21150 CTTGAACAGTCTTAAA 39 500 1245672 1347 1362 2116221177 GTGGCATGGCTACAGA 56 501 1245698 1391 1406 21206 21221GATCTCTTAGCTGTGC 64 502 1245724 1430 1445 21245 21260 AATATGTCCAGGTTGA64 503 1245750 1505 1520 21320 21335 CAGAATAGAGTTGCAC 50 504 12457761564 1579 21379 21394 AGGGTCCACTTTTGGT 11 505 1245802 1623 1638 2143821453 TAGAGTCGGTCACCTT 65 506 1245828 1719 1734 21534 21549TGTCTAAACATCTCTG 58 507 1245841 1765 1780 21580 21595 GTACAGTTCCTTTTCC51 38 1245854 1778 1793 21593 21608 TATGTAATAGCCAGTA 50 508 1245880 21832198 21998 22013 GTAGTGGGAGTCGGAT 48 509 1245906 2254 2269 22069 22084CAAGAGGATAGTCCAT 58 510 1245932 N/A N/A 3487 3502 AGACTAAGGGACCAGG 80511 1245958 N/A N/A 3611 3626 TCATTTAGCAGCTTGG 79 512 1245984 N/A N/A4123 4138 ACAATTTTTCCAATCC 86 513 1246010 N/A N/A 4642 4657AATACGACTTCCTTCT 26 514 1246036 N/A N/A 5105 5120 TGAAAACTCAGCCAGC 77515 1246062 N/A N/A 5287 5302 TTATAACTGAGCTAGA 8 516 1246065 N/A N/A5659 5674 ATAAGTTACCAGAGCA 89 48 1246088 N/A N/A 5843 5858CCCAAACATGGATGTT 72 517 1246114 N/A N/A 6039 6054 AATTATACTTTTCCGT 66518 1246140 N/A N/A 6328 6343 CTTTCATAGGGAGACC 73 519 1246166 N/A N/A6608 6623 TCTAAAGCAGGCTACT 32 520 1246192 N/A N/A 7757 7772CCAATTTAAATCAGGC 73 521 1246218 N/A N/A 7976 7991 CAAAGTTAATAGGACT 50522 1246244 N/A N/A 8280 8295 GTCTAAAGTGCTGGTT 39 523 1246270 N/A N/A8747 8762 GAACACTTTCACTGGG 0 524 1246296 N/A N/A 9110 9125ACCAAGTAGCTTACAT 2 525 1246322 N/A N/A 9377 9392 GGATCTAGAACACTTG 32 5261246348 N/A N/A 9598 9613 ATGTGAAGAGCTGGTA 42 527 1246374 N/A N/A 97619776 CCCAAGCTACCTCCAA 15 528 1246400 N/A N/A 10001 10016GTGAAATCTTGTGTAA 44 529 1246426 N/A N/A 10360 10375 AGACAATGACATAGAC 14530 1246452 N/A N/A 10836 10851 ACTGAGTAAACGACTC 45 531 1246478 N/A N/A11428 11443 CCCTTTATGTCTTTGG 35 532 1246504 N/A N/A 11790 11805CTATTGATTGGCTTAA 31 533 1246530 N/A N/A 12038 12053 AAATTTGCTGGAACTG 15534 1246556 N/A N/A 12478 12493 AGCTAGATACTCAATT 2 535 1246582 N/A N/A12652 12667 GAATATATACTAGGAT 5 536 1246608 N/A N/A 12782 12797CCTCAAATGAGGCGGC 47 537 1246634 N/A N/A 13730 13745 ATTAAGTACTGTGAGA 1538 1246660 N/A N/A 13897 13912 CATCTATCATGCCTTC 18 539 1246686 N/A N/A14048 14063 ATTACATATCAATGCC 36 540 1246712 N/A N/A 14250 14265AGCGAATGTTAAAACT 16 541 1246738 N/A N/A 14439 14454 TCCTTATACTGAAGGC 22542 1246764 N/A N/A 14936 14951 CTCATTATAAGCTAAC 13 543 1246790 N/A N/A15350 15365 AGTAGTGGAGCCAGAC 39 544 1246816 N/A N/A 15425 15440TCATATCCAGTAGGTG 32 545 1246842 N/A N/A 16129 16144 TCCATAATAATAGCTC 69546 1246868 N/A N/A 16905 16920 CGTCAAAAACCGTCAA 20 547 1246894 N/A N/A17923 17938 GAGTATTTCCTCTGGG 23 548 1246920 N/A N/A 18506 18521ACTAATTTAGTCAACT 18 549 1246946 N/A N/A 18846 18861 TTTAACTACCCTCACA 0550 1246972 N/A N/A 19487 19502 TCTAGAATTAAGGGCT 45 551 1246998 N/A N/A19701 19716 CTGATTAATCTTGATG 32 552 1247024 N/A N/A 19911 19926GCATCTTAAGATACCC 82 553 1247050 N/A N/A 20249 20264 GCCTAAACAAACACTA 37554 1247076 N/A N/A 20481 20496 CATAGTGGACTTCATT 34 555

TABLE 8 Inhibition of HSD17B13 RNA by 3-10-3 cEtgapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO:NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop (% IDNumber Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 1245075 1126 3105 3120 GTAGTCCTAGGGAGGA 77 556 1245101 67 82 3161 3176TCTAGGATGATGTTCA 64 557 1245127 118 133 3212 3227 ACCAACGACTCCAAGT 16558 1245153 208 223 3302 3317 GTAGTCTGCCTGCCTA 68 559 1245179 269 284N/A N/A CACACCGCGCTTATTA 11 560 1245205 317 332 7606 7621CGCATGCGCAGTGACG 46 561 1245231 366 381 7655 7670 GATTTAGAGAGCGATA 44562 1245257 409 424 8803 8818 TTATTCACCACGATTG 40 563 1245283 439 4548833 8848 AGAAGATCGGCTGGAT 29 564 1245309 483 498 8877 8892TGTTGACCTCAAATGT 14 565 1245335 529 544 10415 10430 ATCATCGATGGAAGAA 30566 1245361 576 591 10462 10477 GGCCGCACACTGAAGC 9 567 1245387 632 64712050 12065 GCCAACAGCGGCAAAT 30 568 1245413 693 708 12111 12126ATGAGGTTTTGATACC 47 569 1245439 766 781 15647 15662 GTCTCCAATACAGGCC 47570 1245465 798 813 15679 15694 TTCCATCTATCAGACT 33 571 1245491* 866 881N/A N/A AAACTTCTGTAGTCTC 67 572 1245517* 927 942 20742 20757CCACTGCTTCAAATTG 77 573 1245543* 981 996 20796 20811 CATACATCTCTGGCTG 69574 1245569 1021 1036 20836 20851 TTTGCAGCATTGATTC 53 575 1245595 11091124 20924 20939 CAGGTAATTAATCTTG 54 576 1245621 1267 1282 21082 21097TTAGGGAGGTAGCTTT 54 577 1245647 1321 1336 21136 21151 ACTTGAACAGTCTTAA63 578 1245673 1348 1363 21163 21178 TGTGGCATGGCTACAG 24 579 12456991392 1407 21207 21222 TGATCTCTTAGCTGTG 59 580 1245725 1431 1446 2124621261 AAATATGTCCAGGTTG 68 581 1245751 1506 1521 21321 21336CCAGAATAGAGTTGCA 62 582 1245777 1565 1580 21380 21395 GAGGGTCCACTTTTGG23 583 1245803 1624 1639 21439 21454 ATAGAGTCGGTCACCT 60 584 12458291721 1736 21536 21551 ATTGTCTAAACATCTC 84 585 1245855 1779 1794 2159421609 TTATGTAATAGCCAGT 77 586 1245881 2184 2199 21999 22014TGTAGTGGGAGTCGGA 62 587 1245907 2255 2270 22070 22085 ACAAGAGGATAGTCCA64 588 1245933 N/A N/A 3488 3503 CAGACTAAGGGACCAG 75 589 1245959 N/A N/A3612 3627 CTCATTTAGCAGCTTG 70 590 1245985 N/A N/A 4136 4151CAAGGAGTACTTCACA 66 591 1246011 N/A N/A 4643 4658 TAATACGACTTCCTTC 32592 1246037 N/A N/A 5125 5140 GCAAAAGGAGCCAGTT 57 593 1246063 N/A N/A5290 5305 GTTTTATAACTGAGCT 84 594 1246089 N/A N/A 5871 5886CTAAACCCTGGAGCAG 42 595 1246115 N/A N/A 6040 6055 AAATTATACTTTTCCG 85596 1246141 N/A N/A 6337 6352 GAAGAAGGACTTTCAT 40 597 1246167 N/A N/A6609 6624 CTCTAAAGCAGGCTAC 51 598 1246193 N/A N/A 7758 7773TCCAATTTAAATCAGG 61 599 1246219 N/A N/A 7977 7992 GCAAAGTTAATAGGAC 52600 1246245 N/A N/A 8282 8297 TGGTCTAAAGTGCTGG 61 601 1246271 N/A N/A8895 8910 CCCAAAAATGTCCTAG 18 602 1246297 N/A N/A 9111 9126GACCAAGTAGCTTACA 28 603 1246323 N/A N/A 9379 9394 ATGGATCTAGAACACT 43604 1246349 N/A N/A 9600 9615 ATATGTGAAGAGCTGG 51 605 1246375 N/A N/A9762 9777 ACCCAAGCTACCTCCA 9 606 1246401 N/A N/A 10002 10017AGTGAAATCTTGTGTA 41 607 1246427 N/A N/A 10380 10395 GATCATTGCAGAAAGA 23608 1246453 N/A N/A 10849 10864 ACATATGGTGTACACT 19 609 1246479 N/A N/A11468 11483 GCAAATACAGCAGTAC 56 610 1246505 N/A N/A 11791 11806TCTATTGATTGGCTTA 39 611 1246531 N/A N/A 12039 12054 CAAATTTGCTGGAACT 39612 1246557 N/A N/A 12482 12497 AAGGAGCTAGATACTC 19 613 1246583 N/A N/A12654 12669 CAGAATATATACTAGG 55 614 1246609 N/A N/A 12795 12810TAAGAGTCAGTATCCT 52 615 1246635 N/A N/A 13731 13746 TATTAAGTACTGTGAG 0616 1246661 N/A N/A 13915 13930 CATTATCCTTACTCCC 16 617 1246687 N/A N/A14049 14064 CATTACATATCAATGC 29 618 1246713 N/A N/A 14262 14277AGTTAGGGAGCCAGCG 38 619 1246739 N/A N/A 14465 14480 CTGGAGGTATGTCATA 23620 1246765 N/A N/A 15022 15037 TGATAAAATAGGGTGC 44 621 1246791 N/A N/A15351 15366 GAGTAGTGGAGCCAGA 44 622 1246817 N/A N/A 15427 15442TTTCATATCCAGTAGG 36 623 1246843 N/A N/A 16189 16204 AATAACTGTTCTCCCC 20624 1246869 N/A N/A 16956 16971 GACAACAAACAATGGG 39 625 1246895 N/A N/A17924 17939 AGAGTATTTCCTCTGG 32 626 1246921 N/A N/A 18507 18522CACTAATTTAGTCAAC 7 627 1246947 N/A N/A 18847 18862 TTTTAACTACCCTCAC 2628 1246973 N/A N/A 19488 19503 ATCTAGAATTAAGGGC 41 629 1246999 N/A N/A19702 19717 GCTGATTAATCTTGAT 48 630 1247025 N/A N/A 19921 19936TCCAAGGAGTGCATCT 46 631 1247051 N/A N/A 20356 20371 TTATTGCCTGAACACA 58632 1247077 N/A N/A 20482 20497 TCATAGTGGACTTCAT 36 633

TABLE 9 Inhibition of HSD17B13 RNA by 3-10-3 cEtgapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO:NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop (% IDNumber Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 1245076 1227 3106 3121 TGTAGTCCTAGGGAGG 86 634 1245102 68 83 3162 3177TTCTAGGATGATGTTC 72 635 1245128 119 134 3213 3228 CACCAACGACTCCAAG 16636 1245154 211 226 3305 3320 TAAGTAGTCTGCCTGC 19 637 1245180 271 286N/A N/A TCCACACCGCGCTTAT 32 638 1245206 318 333 7607 7622ACGCATGCGCAGTGAC 52 639 1245232 367 382 7656 7671 TGATTTAGAGAGCGAT 35640 1245258 410 425 8804 8819 ATTATTCACCACGATT 29 641 1245284 440 4558834 8849 GAGAAGATCGGCTGGA 6 642 1245310 484 499 8878 8893ATGTTGACCTCAAATG 0 643 1245336 530 545 10416 10431 CATCATCGATGGAAGA 14644 1245362 577 592 10463 10478 TGGCCGCACACTGAAG 0 645 1245388 638 65312056 12071 GTGAAAGCCAACAGCG 62 646 1245414 696 711 12114 12129GACATGAGGTTTTGAT 52 647 1245440 767 782 15648 15663 TGTCTCCAATACAGGC 39648 1245466 799 814 15680 15695 ATTCCATCTATCAGAC 7 649 1245492* 867 882N/A N/A GAAACTTCTGTAGTCT 86 650 1245518* 931 946 20746 20761CCAACCACTGCTTCAA 98 651 1245544* 982 997 20797 20812 GCATACATCTCTGGCT 27652 1245570 1023 1038 20838 20853 GCTTTGCAGCATTGAT 61 653 1245596 11101125 20925 20940 ACAGGTAATTAATCTT 39 654 1245622 1268 1283 21083 21098TTTAGGGAGGTAGCTT 24 655 1245648 1322 1337 21137 21152 TACTTGAACAGTCTTA48 656 1245674 1349 1364 21164 21179 CTGTGGCATGGCTACA 66 657 12457001393 1408 21208 21223 TTGATCTCTTAGCTGT 74 658 1245726 1461 1476 2127621291 CTAGGGAAATCTTTCA 48 659 1245752 1507 1522 21322 21337TCCAGAATAGAGTTGC 46 660 1245778 1566 1581 21381 21396 AGAGGGTCCACTTTTG34 661 1245804 1625 1640 21440 21455 AATAGAGTCGGTCACC 58 662 12458301728 1743 21543 21558 GCCTAAAATTGTCTAA 32 663 1245841 1765 1780 2158021595 GTACAGTTCCTTTTCC 49 38 1245856 1780 1795 21595 21610CTTATGTAATAGCCAG 74 664 1245882 2185 2200 22000 22015 ATGTAGTGGGAGTCGG72 665 1245908 2256 2271 22071 22086 AACAAGAGGATAGTCC 54 666 1245934 N/AN/A 3489 3504 ACAGACTAAGGGACCA 68 667 1245960 N/A N/A 3613 3628CCTCATTTAGCAGCTT 81 668 1245986 N/A N/A 4138 4153 CTCAAGGAGTACTTCA 82669 1246012 N/A N/A 4644 4659 TTAATACGACTTCCTT 35 670 1246038 N/A N/A5126 5141 GGCAAAAGGAGCCAGT 43 671 1246064 N/A N/A 5655 5670GTTACCAGAGCATTCA 73 672 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA 89 481246090 N/A N/A 5872 5887 GCTAAACCCTGGAGCA 5 673 1246116 N/A N/A 60896104 CAAGTTTTCACCTCAG 93 674 1246142 N/A N/A 6357 6372 GGGAAAGAAGTCTCCT13 675 1246168 N/A N/A 6610 6625 TCTCTAAAGCAGGCTA 60 676 1246194 N/A N/A7770 7785 TAGCAGCTAAAATCCA 66 677 1246220 N/A N/A 7978 7993TGCAAAGTTAATAGGA 43 678 1246246 N/A N/A 8487 8502 CTATATAAATTCTGAC 0 6791246272 N/A N/A 8939 8954 TAAGAGAAGGTGCACA 12 680 1246298 N/A N/A 91309145 GATACTGGTGGACAAG 13 681 1246324 N/A N/A 9410 9425 GTATAGCTGCATTTCT35 682 1246350 N/A N/A 9601 9616 CATATGTGAAGAGCTG 25 683 1246376 N/A N/A9776 9791 AACTAGAACTCCCAAC 0 684 1246402 N/A N/A 10025 10040GGCTTTATCATTCTAA 20 685 1246428 N/A N/A 10384 10399 TAAGGATCATTGCAGA 0686 1246454 N/A N/A 10855 10870 CCATTTACATATGGTG 28 687 1246480 N/A N/A11469 11484 GGCAAATACAGCAGTA 64 688 1246506 N/A N/A 11792 11807CTCTATTGATTGGCTT 65 689 1246532 N/A N/A 12168 12183 CTTACCTTGTGCTTGG 34690 1246558 N/A N/A 12486 12501 GACTAAGGAGCTAGAT 25 691 1246584 N/A N/A12655 12670 GCAGAATATATACTAG 55 692 1246610 N/A N/A 12799 12814GCTGTAAGAGTCAGTA 89 693 1246636 N/A N/A 13733 13748 CTTATTAAGTACTGTG 0694 1246662 N/A N/A 13916 13931 CCATTATCCTTACTCC 27 695 1246688 N/A N/A14089 14104 CTACATGGATCCAACA 5 696 1246714 N/A N/A 14266 14281GAGGAGTTAGGGAGCC 36 697 1246740 N/A N/A 14469 14484 ACAACTGGAGGTATGT 0698 1246766 N/A N/A 15023 15038 TTGATAAAATAGGGTG 46 699 1246792 N/A N/A15353 15368 AGGAGTAGTGGAGCCA 16 700 1246818 N/A N/A 15443 15458TATCAGAAACTTATAC 0 701 1246844 N/A N/A 16191 16206 GAAATAACTGTTCTCC 32702 1246870 N/A N/A 16969 16984 TCCAATATATACTGAC 72 703 1246896 N/A N/A17930 17945 GCTGAGAGAGTATTTC 51 704 1246922 N/A N/A 18508 18523ACACTAATTTAGTCAA 16 705 1246948 N/A N/A 18848 18863 CTTTTAACTACCCTCA 16706 1246974 N/A N/A 19490 19505 CCATCTAGAATTAAGG 0 707 1247000 N/A N/A19731 19746 ACTGAAGGTCTGAGCT 20 708 1247026 N/A N/A 19922 19937CTCCAAGGAGTGCATC 53 709 1247052 N/A N/A 20359 20374 AAATTATTGCCTGAAC 32710 1247078 N/A N/A 20484 20499 CTTCATAGTGGACTTC 79 711

TABLE 10 Inhibition of HSD17B13 RNA by 3-10-3 cEtgapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO:NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop (% IDNumber Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 1245077 1328 3107 3122 GTGTAGTCCTAGGGAG 67 712 1245103 71 86 3165 3180GATTTCTAGGATGATG 57 713 1245129 120 135 3214 3229 TCACCAACGACTCCAA 19714 1245155 212 227 3306 3321 ATAAGTAGTCTGCCTG 43 715 1245181 272 287N/A N/A CTCCACACCGCGCTTA 7 716 1245207 319 334 7608 7623TACGCATGCGCAGTGA 60 717 1245233 368 383 7657 7672 CTGATTTAGAGAGCGA 61718 1245259 411 426 8805 8820 CATTATTCACCACGAT 33 719 1245285 441 4568835 8850 TGAGAAGATCGGCTGG 37 720 1245311 485 500 8879 8894GATGTTGACCTCAAAT 0 721 1245337 531 546 10417 10432 CCATCATCGATGGAAG 8722 1245363 578 593 10464 10479 GTGGCCGCACACTGAA 41 723 1245389 642 65712060 12075 CTCTGTGAAAGCCAAC 50 724 1245415 698 713 12116 12131GAGACATGAGGTTTTG 77 725 1245441 768 783 15649 15664 CTGTCTCCAATACAGG 29726 1245467 801 816 15682 15697 GTATTCCATCTATCAG 52 727 1245493* 877 892N/A N/A CGTTCAGGAAGAAACT 70 728 1245519* 932 947 20747 20762GCCAACCACTGCTTCA 97 729 1245545* 983 998 20798 20813 TGCATACATCTCTGGC 53730 1245571 1024 1039 20839 20854 AGCTTTGCAGCATTGA 62 731 1245597 11111126 20926 20941 GACAGGTAATTAATCT 60 732 1245623 1269 1284 21084 21099TTTTAGGGAGGTAGCT 39 733 1245649 1323 1338 21138 21153 CTACTTGAACAGTCTT80 734 1245675 1350 1365 21165 21180 TCTGTGGCATGGCTAC 67 735 12457011394 1409 21209 21224 CTTGATCTCTTAGCTG 51 736 1245727 1462 1477 2127721292 GCTAGGGAAATCTTTC 66 737 1245753 1508 1523 21323 21338GTCCAGAATAGAGTTG 60 738 1245779 1567 1582 21382 21397 TAGAGGGTCCACTTTT36 739 1245805 1626 1641 21441 21456 AAATAGAGTCGGTCAC 59 740 12458311729 1744 21544 21559 AGCCTAAAATTGTCTA 53 741 1245857 1781 1796 2159621611 TCTTATGTAATAGCCA 77 742 1245883 2186 2201 22001 22016GATGTAGTGGGAGTCG 67 743 1245909 2257 2272 22072 22087 AAACAAGAGGATAGTC48 744 1245935 N/A N/A 3492 3507 TATACAGACTAAGGGA 24 745 1245961 N/A N/A3629 3644 GATAATATGTGACTTG 68 746 1245987 N/A N/A 4139 4154TCTCAAGGAGTACTTC 80 747 1246013 N/A N/A 4645 4660 TTTAATACGACTTCCT 72748 1246039 N/A N/A 5156 5171 CAAACTGCTACTGTGT 57 749 1246065 N/A N/A5659 5674 ATAAGTTACCAGAGCA 91 48 1246091 N/A N/A 5875 5890TAGGCTAAACCCTGGA 64 750 1246117 N/A N/A 6134 6149 CTCTAATGTTTCTTGA 53751 1246143 N/A N/A 6422 6437 TAAACTGTATGCCTCT 49 752 1246169 N/A N/A6622 6637 CAGTAGGCAGTTTCTC 72 753 1246195 N/A N/A 7776 7791TTCAGTTAGCAGCTAA 72 754 1246221 N/A N/A 7979 7994 CTGCAAAGTTAATAGG 57755 1246247 N/A N/A 8529 8544 GTTTATCAGTAAAGTG 64 756 1246273 N/A N/A8940 8955 TTAAGAGAAGGTGCAC 38 757 1246299 N/A N/A 9146 9161GCCAAGCTTTGTGTCA 64 758 1246325 N/A N/A 9413 9428 TCTGTATAGCTGCATT 47759 1246351 N/A N/A 9603 9618 CACATATGTGAAGAGC 71 760 1246377 N/A N/A9780 9795 ATAGAACTAGAACTCC 22 761 1246403 N/A N/A 10058 10073GATAATTTGGTGTCAT 59 762 1246429 N/A N/A 10385 10400 TTAAGGATCATTGCAG 14763 1246455 N/A N/A 10931 10946 CATAAGGCCGATTCAT 32 764 1246481 N/A N/A11482 11497 GGAAAGGATATTTGGC 58 765 1246507 N/A N/A 11793 11808ACTCTATTGATTGGCT 57 766 1246533 N/A N/A 12178 12193 TGATTTTGACCTTACC 11767 1246559 N/A N/A 12487 12502 TGACTAAGGAGCTAGA 31 768 1246585 N/A N/A12685 12700 ATTAAGCTTAGTATAT 10 769 1246611 N/A N/A 12810 12825AGCTAACTCAGGCTGT 14 770 1246637 N/A N/A 13738 13753 GCATACTTATTAAGTA 32771 1246663 N/A N/A 13917 13932 TCCATTATCCTTACTC 15 772 1246689 N/A N/A14090 14105 TCTACATGGATCCAAC 26 773 1246715 N/A N/A 14280 14295TGTAAAGGCTGGGTGA 26 774 1246741 N/A N/A 14473 14488 TATGACAACTGGAGGT 14775 1246767 N/A N/A 15024 15039 GTTGATAAAATAGGGT 42 776 1246793 N/A N/A15354 15369 AAGGAGTAGTGGAGCC 38 777 1246819 N/A N/A 15445 15460GTTATCAGAAACTTAT 31 778 1246845 N/A N/A 16219 16234 TTATAGACTGGGTAGG 51779 1246871 N/A N/A 17017 17032 GTTTAGCAATTTAGCA 50 780 1246897 N/A N/A17956 17971 ATTTAGAAACTGCTCC 21 781 1246923 N/A N/A 18521 18536GCTTAGTACCAAGACA 62 782 1246949 N/A N/A 18849 18864 CCTTTTAACTACCCTC 22783 1246975 N/A N/A 19533 19548 AGGCTAAAATGGTCAT 36 784 1247001 N/A N/A19736 19751 CTAAAACTGAAGGTCT 40 785 1247027 N/A N/A 19936 19951TAGGAACATTCCCTCT 24 786 1247053 N/A N/A 20362 20377 TCTAAATTATTGCCTG 43787 1247079 N/A N/A 20485 20500 ACTTCATAGTGGACTT 61 788

TABLE 11 Inhibition of HSD17B13 RNA by 3-10-3 cEtgapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO:NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop (% IDNumber Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 1245078 1429 3108 3123 TGTGTAGTCCTAGGGA 50 789 1245104 72 87 3166 3181GGATTTCTAGGATGAT 58 790 1245130 121 136 3215 3230 TTCACCAACGACTCCA 62791 1245156 213 228 3307 3322 CATAAGTAGTCTGCCT 31 792 1245182 273 288N/A N/A CCTCCACACCGCGCTT 16 793 1245208 320 335 7609 7624ATACGCATGCGCAGTG 38 794 1245234 369 384 7658 7673 CCTGATTTAGAGAGCG 42795 1245260 412 427 8806 8821 GCATTATTCACCACGA 59 796 1245286 442 4578836 8851 CTGAGAAGATCGGCTG 37 797 1245312 486 501 8880 8895GGATGTTGACCTCAAA 5 798 1245338 532 547 10418 10433 TCCATCATCGATGGAA 31799 1245364 579 594 10465 10480 CGTGGCCGCACACTGA 42 800 1245390 645 66012063 12078 GACCTCTGTGAAAGCC 46 801 1245416 715 730 12133 12148TTCACAAAAACTGGGC 37 802 1245442 769 784 15650 15665 TCTGTCTCCAATACAG 13803 1245468 802 817 15683 15698 AGTATTCCATCTATCA 62 804 1245494* 891 90620706 20721 AAATCGCTGAGGCGCG 89 805 1245520* 933 948 20748 20763GGCCAACCACTGCTTC 93 806 1245546* 984 999 20799 20814 ATGCATACATCTCTGG 53807 1245572 1025 1040 20840 20855 AAGCTTTGCAGCATTG 59 808 1245598 11121127 20927 20942 AGACAGGTAATTAATC 29 809 1245624 1270 1285 21085 21100CTTTTAGGGAGGTAGC 62 810 1245650 1324 1339 21139 21154 GCTACTTGAACAGTCT66 811 1245676 1351 1366 21166 21181 TTCTGTGGCATGGCTA 78 812 12457021395 1410 21210 21225 ACTTGATCTCTTAGCT 59 813 1245728 1463 1478 2127821293 GGCTAGGGAAATCTTT 57 814 1245754 1509 1524 21324 21339AGTCCAGAATAGAGTT 58 815 1245780 1568 1583 21383 21398 ATAGAGGGTCCACTTT21 816 1245806 1627 1642 21442 21457 AAAATAGAGTCGGTCA 71 817 12458321730 1745 21545 21560 GAGCCTAAAATTGTCT 49 818 1245858 1782 1797 2159721612 TTCTTATGTAATAGCC 71 819 1245884 2187 2202 22002 22017TGATGTAGTGGGAGTC 65 820 1245910 2349 2364 22164 22179 CTACAAGAGGTTATTT31 821 1245936 N/A N/A 3493 3508 ATATACAGACTAAGGG 24 822 1245962 N/A N/A3671 3686 AAGTTATTATCCCCAC 60 823 1245988 N/A N/A 4220 4235AACTAAACATGACAGC 72 824 1246014 N/A N/A 4646 4661 TTTTAATACGACTTCC 57825 1246040 N/A N/A 5164 5179 ATAAGAGCCAAACTGC 49 826 1246066 N/A N/A5660 5675 CATAAGTTACCAGAGC 80 827 1246092 N/A N/A 5878 5893CTGTAGGCTAAACCCT 47 828 1246118 N/A N/A 6135 6150 GCTCTAATGTTTCTTG 62829 1246144 N/A N/A 6423 6438 GTAAACTGTATGCCTC 74 830 1246170 N/A N/A6624 6639 TACAGTAGGCAGTTTC 60 831 1246196 N/A N/A 7777 7792CTTCAGTTAGCAGCTA 50 832 1246222 N/A N/A 8039 8054 ACTACATTAACACCAA 46833 1246248 N/A N/A 8534 8549 TGCAAGTTTATCAGTA 70 834 1246274 N/A N/A8941 8956 CTTAAGAGAAGGTGCA 43 835 1246300 N/A N/A 9188 9203CTTAACAAACCTCCAC 3 836 1246326 N/A N/A 9424 9439 ATTATATGAGGTCTGT 59 8371246352 N/A N/A 9604 9619 TCACATATGTGAAGAG 27 838 1246378 N/A N/A 97819796 CATAGAACTAGAACTC 19 839 1246404 N/A N/A 10059 10074TGATAATTTGGTGTCA 3 840 1246430 N/A N/A 10386 10401 CTTAAGGATCATTGCA 29841 1246456 N/A N/A 10971 10986 GTAATCTTGAGGCAGG 51 842 1246482 N/A N/A11511 11526 TATTATGAGGATCTGG 44 843 1246508 N/A N/A 11853 11868AGCAGAATTGTGAACG 67 844 1246534 N/A N/A 12194 12209 CATACCCATTCTAACT 6845 1246560 N/A N/A 12488 12503 TTGACTAAGGAGCTAG 20 846 1246586 N/A N/A12686 12701 CATTAAGCTTAGTATA 19 847 1246612 N/A N/A 12813 12828CATAGCTAACTCAGGC 29 848 1246638 N/A N/A 13748 13763 CTTACATATTGCATAC 35849 1246664 N/A N/A 13951 13966 CTAAGTTAGCCCCCAG 15 850 1246690 N/A N/A14091 14106 ATCTACATGGATCCAA 12 851 1246716 N/A N/A 14283 14298GAATGTAAAGGCTGGG 42 852 1246742 N/A N/A 14477 14492 GGAGTATGACAACTGG 28853 1246768 N/A N/A 15170 15185 CGTTTAAATCAGAGCA 54 854 1246794 N/A N/A15355 15370 TAAGGAGTAGTGGAGC 18 855 1246820 N/A N/A 15492 15507ATTAATGCCACCCTAC 6 856 1246846 N/A N/A 16223 16238 CTTTTTATAGACTGGG 67857 1246872 N/A N/A 17019 17034 AGGTTTAGCAATTTAG 54 858 1246898 N/A N/A17985 18000 ATAGTTATCTTCTCAC 48 859 1246924 N/A N/A 18585 18600TATTAATATGACTTGC 25 860 1246950 N/A N/A 18850 18865 GCCTTTTAACTACCCT 0861 1246976 N/A N/A 19534 19549 TAGGCTAAAATGGTCA 59 862 1247002 N/A N/A19739 19754 GATCTAAAACTGAAGG 44 863 1247028 N/A N/A 19970 19985AATTTCATACAGTTCG 66 864 1247054 N/A N/A 20363 20378 GTCTAAATTATTGCCT 45865 1247080 N/A N/A 20489 20504 CATAACTTCATAGTGG 31 866

TABLE 12 Inhibition of HSD17B13 RNA by 3-10-3 cEtgapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO:NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop (% IDNumber Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 1245079 1530 3109 3124 TTGTGTAGTCCTAGGG 64 867 1245105 75 90 3169 3184GAAGGATTTCTAGGAT 71 868 1245131 122 137 3216 3231 CTTCACCAACGACTCC 8 8691245157 214 229 3308 3323 TCATAAGTAGTCTGCC 62 870 1245183 274 289 75637578 TCCTCCACACCGCGCT 20 871 1245209 321 336 7610 7625 CATACGCATGCGCAGT60 872 1245235 370 385 7659 7674 ACCTGATTTAGAGAGC 65 873 1245261 413 4288807 8822 AGCATTATTCACCACG 53 874 1245287 443 458 8837 8852GCTGAGAAGATCGGCT 10 875 1245313 487 502 8881 8896 AGGATGTTGACCTCAA 4 8761245339 533 548 10419 10434 CTCCATCATCGATGGA 0 877 1245365 593 608 1047910494 GTAAGGAATCCCTTCG 22 878 1245391 646 661 12064 12079AGACCTCTGTGAAAGC 50 879 1245417 723 738 12141 12156 ACCCAGTATTCACAAA 10880 1245443 770 785 15651 15666 ATCTGTCTCCAATACA 55 881 1245469 803 81815684 15699 AAGTATTCCATCTATC 52 882 1245495* 892 907 20707 20722AAAATCGCTGAGGCGC 97 883 1245521* 934 949 20749 20764 TGGCCAACCACTGCTT 98884 1245547* 985 1000 20800 20815 CATGCATACATCTCTG 55 885 1245573 10291044 20844 20859 AATAAAGCTTTGCAGC 26 886 1245599 1117 1132 20932 20947CAGGAAGACAGGTAAT 60 887 1245625 1271 1286 21086 21101 ACTTTTAGGGAGGTAG20 888 1245651 1325 1340 21140 21155 TGCTACTTGAACAGTC 81 889 12456771353 1368 21168 21183 TATTCTGTGGCATGGC 71 890 1245703 1396 1411 2121121226 AACTTGATCTCTTAGC 64 891 1245729 1464 1479 21279 21294AGGCTAGGGAAATCTT 62 892 1245755 1510 1525 21325 21340 AAGTCCAGAATAGAGT60 893 1245781 1569 1584 21384 21399 TATAGAGGGTCCACTT 17 894 12458071628 1643 21443 21458 TAAAATAGAGTCGGTC 81 895 1245833 1731 1746 2154621561 TGAGCCTAAAATTGTC 30 896 1245841 1765 1780 21580 21595GTACAGTTCCTTTTCC 57 38 1245859 1784 1799 21599 21614 GTTTCTTATGTAATAG 46897 1245885 2188 2203 22003 22018 TTGATGTAGTGGGAGT 68 898 1245911 23502365 22165 22180 ACTACAAGAGGTTATT 46 899 1245937 N/A N/A 3494 3509CATATACAGACTAAGG 57 900 1245963 N/A N/A 3672 3687 TAAGTTATTATCCCCA 70901 1245989 N/A N/A 4249 4264 CTCTAAGTGTAAGAGA 28 902 1246015 N/A N/A4647 4662 TTTTTAATACGACTTC 52 903 1246041 N/A N/A 5165 5180CATAAGAGCCAAACTG 27 904 1246065 N/A N/A 5659 5674 ATAAGTTACCAGAGCA 90 481246067 N/A N/A 5661 5676 GCATAAGTTACCAGAG 79 905 1246093 N/A N/A 58895904 GTATTTCGCTACTGTA 76 906 1246119 N/A N/A 6149 6164 CCTAAGATAAAATTGC18 907 1246145 N/A N/A 6425 6440 TGGTAAACTGTATGCC 76 908 1246171 N/A N/A6625 6640 GTACAGTAGGCAGTTT 50 909 1246197 N/A N/A 7782 7797AACTACTTCAGTTAGC 53 910 1246223 N/A N/A 8043 8058 GAAGACTACATTAACA 36911 1246249 N/A N/A 8562 8577 AAATTTCAGTACCCAG 46 912 1246275 N/A N/A8942 8957 TCTTAAGAGAAGGTGC 39 913 1246301 N/A N/A 9189 9204CCTTAACAAACCTCCA 27 914 1246327 N/A N/A 9426 9441 CAATTATATGAGGTCT 36915 1246353 N/A N/A 9610 9625 GCCAATTCACATATGT 34 916 1246379 N/A N/A9887 9902 TATATGTTGATGTTAC 34 917 1246405 N/A N/A 10060 10075ATGATAATTTGGTGTC 55 918 1246431 N/A N/A 10387 10402 TCTTAAGGATCATTGC 0919 1246457 N/A N/A 10973 10988 TTGTAATCTTGAGGCA 27 920 1246483 N/A N/A11512 11527 TTATTATGAGGATCTG 50 921 1246509 N/A N/A 11854 11869AAGCAGAATTGTGAAC 18 922 1246535 N/A N/A 12201 12216 CATACCACATACCCAT 0923 1246561 N/A N/A 12489 12504 CTTGACTAAGGAGCTA 24 924 1246587 N/A N/A12687 12702 TCATTAAGCTTAGTAT 31 925 1246613 N/A N/A 12814 12829ACATAGCTAACTCAGG 38 926 1246639 N/A N/A 13763 13778 GTACTATAGTATTTAC 27927 1246665 N/A N/A 13952 13967 TCTAAGTTAGCCCCCA 36 928 1246691 N/A N/A14092 14107 CATCTACATGGATCCA 63 929 1246717 N/A N/A 14316 14331TTAAGATGTCCAGGCA 35 930 1246743 N/A N/A 14479 14494 AAGGAGTATGACAACT 28931 1246769 N/A N/A 15211 15226 CATAAAGCTGGATTGT 0 932 1246795 N/A N/A15356 15371 GTAAGGAGTAGTGGAG 37 933 1246821 N/A N/A 15493 15508CATTAATGCCACCCTA 8 934 1246847 N/A N/A 16254 16269 AGTAGATTTGGTAGAG 67935 1246873 N/A N/A 17041 17056 GCTTATCGAGTTTAGC 17 936 1246899 N/A N/A17987 18002 GTATAGTTATCTTCTC 59 937 1246925 N/A N/A 18662 18677ATACTATTCTCCAACT 25 938 1246951 N/A N/A 18871 18886 ATAAGAAGAGAGCTCA 14939 1246977 N/A N/A 19544 19559 GTTTAGCTGATAGGCT 47 940 1247003 N/A N/A19749 19764 TATGAGTAAAGATCTA 10 941 1247029 N/A N/A 20004 20019GTAATCAGTTTTCCTC 79 942 1247055 N/A N/A 20373 20388 GTAAGGTAAAGTCTAA 37943 1247081 N/A N/A 20490 20505 ACATAACTTCATAGTG 27 944

TABLE 13 Inhibition of HSD17B13 RNA by 3-10-3 cEtgapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO:NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop (% IDNumber Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 1245080 1631 3110 3125 CTTGTGTAGTCCTAGG 71 945 1245106 91 106 3185 3200ATGGTGATCAGAAGCA 85 946 1245132 123 138 3217 3232 ACTTCACCAACGACTC 15947 1245158 215 230 3309 3324 TTCATAAGTAGTCTGC 64 948 1245184 275 2907564 7579 TTCCTCCACACCGCGC 47 949 1245210 322 337 7611 7626ACATACGCATGCGCAG 20 950 1245236 371 386 7660 7675 CACCTGATTTAGAGAG 11951 1245262 416 431 8810 8825 CCCAGCATTATTCACC 19 952 1245288 444 4598838 8853 TGCTGAGAAGATCGGC 7 953 1245314 488 503 8882 8897TAGGATGTTGACCTCA 19 954 1245340 534 549 10420 10435 TCTCCATCATCGATGG 24955 1245366 594 609 10480 10495 GGTAAGGAATCCCTTC 43 956 1245392 649 66412067 12082 GTCAGACCTCTGTGAA 34 957 1245418 724 739 12142 12157AACCCAGTATTCACAA 0 958 1245444 771 786 15652 15667 CATCTGTCTCCAATAC 32959 1245470 804 819 15685 15700 TAAGTATTCCATCTAT 31 960 1245496* 893 90820708 20723 TAAAATCGCTGAGGCG 87 961 1245522* 935 950 20750 20765GTGGCCAACCACTGCT 99 962 1245548* 986 1001 20801 20816 TCATGCATACATCTCT70 963 1245574 1055 1070 20870 20885 ATATTATCAGGACTGA 47 964 12456001136 1151 20951 20966 CGTAAATATTCTTGAG 61 965 1245626 1272 1287 2108721102 TACTTTTAGGGAGGTA 28 966 1245652 1326 1341 21141 21156ATGCTACTTGAACAGT 47 967 1245678 1354 1369 21169 21184 ATATTCTGTGGCATGG69 968 1245704 1403 1418 21218 21233 CTGCTGAAACTTGATC 50 969 12457301465 1480 21280 21295 GAGGCTAGGGAAATCT 56 970 1245756 1516 1531 2133121346 GTAATAAAGTCCAGAA 66 971 1245782 1570 1585 21385 21400ATATAGAGGGTCCACT 18 972 1245808 1629 1644 21444 21459 TTAAAATAGAGTCGGT65 973 1245834 1732 1747 21547 21562 TTGAGCCTAAAATTGT 36 974 12458411765 1780 21580 21595 GTACAGTTCCTTTTCC 58 38 1245860 1792 1807 2160721622 GGTCCATTGTTTCTTA 36 975 1245886 2189 2204 22004 22019CTTGATGTAGTGGGAG 83 976 1245912 2351 2366 22166 22181 AACTACAAGAGGTTAT57 977 1245938 N/A N/A 3495 3510 ACATATACAGACTAAG 46 978 1245964 N/A N/A3673 3688 CTAAGTTATTATCCCC 70 979 1245990 N/A N/A 4296 4311GTATAGTATTCTTCAC 81 980 1246016 N/A N/A 4649 4664 CATTTTTAATACGACT 57981 1246042 N/A N/A 5166 5181 GCATAAGAGCCAAACT 67 982 1246065 N/A N/A5659 5674 ATAAGTTACCAGAGCA 87 48 1246068 N/A N/A 5662 5677AGCATAAGTTACCAGA 87 983 1246094 N/A N/A 5891 5906 TTGTATTTCGCTACTG 58984 1246120 N/A N/A 6170 6185 CCTAAATTCAAAGACC 64 985 1246146 N/A N/A6429 6444 GTAATGGTAAACTGTA 70 986 1246172 N/A N/A 6737 6752TGAGATTACCCCTGGC 53 987 1246198 N/A N/A 7785 7800 CATAACTACTTCAGTT 3 9881246224 N/A N/A 8121 8136 CTTAGTTCATTGTGAT 69 989 1246250 N/A N/A 85648579 CTAAATTTCAGTACCC 33 990 1246276 N/A N/A 8943 8958 ATCTTAAGAGAAGGTG43 991 1246302 N/A N/A 9190 9205 CCCTTAACAAACCTCC 43 992 1246328 N/A N/A9429 9444 AACCAATTATATGAGG 38 993 1246354 N/A N/A 9632 9647GTGTAGTTTGGTGGGC 33 994 1246380 N/A N/A 9908 9923 CCTATTTGTAATATTG 0 9951246406 N/A N/A 10062 10077 TTATGATAATTTGGTG 0 996 1246432 N/A N/A 1038810403 ATCTTAAGGATCATTG 7 997 1246458 N/A N/A 10976 10991GCATTGTAATCTTGAG 35 998 1246484 N/A N/A 11513 11528 TTTATTATGAGGATCT 43999 1246510 N/A N/A 11856 11871 TTAAGCAGAATTGTGA 7 1000 1246536 N/A N/A12203 12218 ATCATACCACATACCC 45 1001 1246562 N/A N/A 12501 12516GCAGAAATTCACCTTG 74 1002 1246588 N/A N/A 12690 12705 GAATCATTAAGCTTAG 631003 1246614 N/A N/A 12816 12831 CCACATAGCTAACTCA 53 1004 1246640 N/AN/A 13768 13783 CAATAGTACTATAGTA 14 1005 1246666 N/A N/A 13953 13968CTCTAAGTTAGCCCCC 38 1006 1246692 N/A N/A 14126 14141 AATTACTCCGTTCTGC 61007 1246718 N/A N/A 14317 14332 ATTAAGATGTCCAGGC 31 1008 1246744 N/AN/A 14480 14495 CAAGGAGTATGACAAC 6 1009 1246770 N/A N/A 15213 15228TCCATAAAGCTGGATT 13 1010 1246796 N/A N/A 15358 15373 TGGTAAGGAGTAGTGG 341011 1246822 N/A N/A 15494 15509 GCATTAATGCCACCCT 36 1012 1246848 N/AN/A 16255 16270 CAGTAGATTTGGTAGA 49 1013 1246874 N/A N/A 17042 17057AGCTTATCGAGTTTAG 54 1014 1246900 N/A N/A 17988 18003 AGTATAGTTATCTTCT 671015 1246926 N/A N/A 18663 18678 GATACTATTCTCCAAC 44 1016 1246952 N/AN/A 18872 18887 GATAAGAAGAGAGCTC 36 1017 1246978 N/A N/A 19549 19564ATATTGTTTAGCTGAT 14 1018 1247004 N/A N/A 19751 19766 GATATGAGTAAAGATC 231019 1247030 N/A N/A 20006 20021 GAGTAATCAGTTTTCC 65 1020 1247056 N/AN/A 20374 20389 AGTAAGGTAAAGTCTA 55 1021 1247082 N/A N/A 20492 20507TGACATAACTTCATAG 51 1022

TABLE 14 Inhibition of HSD17B13 RNA by 3-10-3 cEtgapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO:NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop (% IDNumber Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 1245081 1732 3111 3126 CCTTGTGTAGTCCTAG 67 1023 1245107 92 107 3186 3201GATGGTGATCAGAAGC 52 1024 1245133 124 139 3218 3233 AACTTCACCAACGACT 01025 1245159 216 231 3310 3325 ATTCATAAGTAGTCTG 35 1026 1245185 276 2917565 7580 TTTCCTCCACACCGCG 18 1027 1245211 323 338 7612 7627CACATACGCATGCGCA 59 1028 1245237 372 387 7661 7676 TCACCTGATTTAGAGA 131029 1245263 418 433 8812 8827 GTCCCAGCATTATTCA 21 1030 1245289 445 4608839 8854 GTGCTGAGAAGATCGG 0 1031 1245315 489 504 8883 8898CTAGGATGTTGACCTC 0 1032 1245341 535 550 10421 10436 CTCTCCATCATCGATG 01033 1245367 595 610 10481 10496 AGGTAAGGAATCCCTT 0 1034 1245393 650 66512068 12083 TGTCAGACCTCTGTGA 0 1035 1245419 725 740 12143 12158GAACCCAGTATTCACA 0 1036 1245445 777 792 15658 15673 CGACTTCATCTGTCTC 191037 1245471 805 820 15686 15701 GTAAGTATTCCATCTA 45 1038 1245497* 894909 20709 20724 TTAAAATCGCTGAGGC 67 1039 1245523* 936 951 20751 20766TGTGGCCAACCACTGC 75 1040 1245549* 987 1002 20802 20817 ATCATGCATACATCTC62 1041 1245575 1075 1090 20890 20905 GTGCCAAACCAATGTT 43 1042 12456011150 1165 20965 20980 CCTATGAAAAACTACG 36 1043 1245627 1277 1292 2109221107 GTATTTACTTTTAGGG 61 1044 1245653 1327 1342 21142 21157AATGCTACTTGAACAG 54 1045 1245679 1355 1370 21170 21185 GATATTCTGTGGCATG46 1046 1245705 1404 1419 21219 21234 CCTGCTGAAACTTGAT 19 1047 12457311466 1481 21281 21296 AGAGGCTAGGGAAATC 63 1048 1245757 1517 1532 2133221347 AGTAATAAAGTCCAGA 43 1049 1245783 1571 1586 21386 21401AATATAGAGGGTCCAC 7 1050 1245809 1630 1645 21445 21460 TTTAAAATAGAGTCGG69 1051 1245835 1733 1748 21548 21563 TTTGAGCCTAAAATTG 26 1052 12458411765 1780 21580 21595 GTACAGTTCCTTTTCC 47 38 1245861 1793 1808 2160821623 GGGTCCATTGTTTCTT 21 1053 1245887 2190 2205 22005 22020TCTTGATGTAGTGGGA 44 1054 1245913 2352 2367 22167 22182 TAACTACAAGAGGTTA22 1055 1245939 N/A N/A 3507 3522 AACTAACCTGACACAT 20 1056 1245965 N/AN/A 3674 3689 CCTAAGTTATTATCCC 18 1057 1245991 N/A N/A 4360 4375ATACATCAACTCCTCT 64 1058 1246017 N/A N/A 4650 4665 TCATTTTTAATACGAC 481059 1246043 N/A N/A 5167 5182 TGCATAAGAGCCAAAC 56 1060 1246065 N/A N/A5659 5674 ATAAGTTACCAGAGCA 84 48 1246069 N/A N/A 5663 5678GAGCATAAGTTACCAG 61 1061 1246095 N/A N/A 5916 5931 CTTGAATGAGTGGTCT 641062 1246121 N/A N/A 6184 6199 CAATTTACTTTCAGCC 71 1063 1246147 N/A N/A6437 6452 AACTAGTGGTAATGGT 32 1064 1246173 N/A N/A 6741 6756GCAATGAGATTACCCC 83 1065 1246199 N/A N/A 7786 7801 ACATAACTACTTCAGT 281066 1246225 N/A N/A 8122 8137 GCTTAGTTCATTGTGA 45 1067 1246251 N/A N/A8587 8602 GGGATAAACTGTTCTT 47 1068 1246277 N/A N/A 8944 8959TATCTTAAGAGAAGGT 29 1069 1246303 N/A N/A 9191 9206 ACCCTTAACAAACCTC 361070 1246329 N/A N/A 9430 9445 TAACCAATTATATGAG 0 1071 1246355 N/A N/A9636 9651 CTCCGTGTAGTTTGGT 28 1072 1246381 N/A N/A 9922 9937GAATTCACTATCTCCC 38 1073 1246407 N/A N/A 10063 10078 CTTATGATAATTTGGT 21074 1246433 N/A N/A 10389 10404 GATCTTAAGGATCATT 0 1075 1246459 N/A N/A11000 11015 TAAATCCAAATCACTC 39 1076 1246485 N/A N/A 11514 11529TTTTATTATGAGGATC 18 1077 1246511 N/A N/A 11857 11872 ATTAAGCAGAATTGTG 81078 1246537 N/A N/A 12205 12220 TTATCATACCACATAC 19 1079 1246563 N/AN/A 12512 12527 CAAGAGTTCTTGCAGA 17 1080 1246589 N/A N/A 12692 12707TCGAATCATTAAGCTT 34 1081 1246615 N/A N/A 12817 12832 ACCACATAGCTAACTC 501082 1246641 N/A N/A 13769 13784 GCAATAGTACTATAGT 39 1083 1246667 N/AN/A 13954 13969 CCTCTAAGTTAGCCCC 97 1084 1246693 N/A N/A 14127 14142AAATTACTCCGTTCTG 28 1085 1246719 N/A N/A 14321 14336 TCAAATTAAGATGTCC 61086 1246745 N/A N/A 14499 14514 TGAGAATTTAAGAGGG 25 1087 1246771 N/AN/A 15217 15232 GTATTCCATAAAGCTG 10 1088 1246797 N/A N/A 15359 15374ATGGTAAGGAGTAGTG 17 1089 1246823 N/A N/A 15495 15510 TGCATTAATGCCACCC 221090 1246849 N/A N/A 16257 16272 GACAGTAGATTTGGTA 34 1091 1246875 N/AN/A 17043 17058 AAGCTTATCGAGTTTA 26 1092 1246901 N/A N/A 17989 18004TAGTATAGTTATCTTC 28 1093 1246927 N/A N/A 18666 18681 TGGGATACTATTCTCC 181094 1246953 N/A N/A 18873 18888 GGATAAGAAGAGAGCT 46 1095 1246979 N/AN/A 19550 19565 GATATTGTTTAGCTGA 59 1096 1247005 N/A N/A 19753 19768CTGATATGAGTAAAGA 21 1097 1247031 N/A N/A 20008 20023 GAGAGTAATCAGTTTT 271098 1247057 N/A N/A 20375 20390 AAGTAAGGTAAAGTCT 20 1099 1247083 N/AN/A 20571 20586 TTTAACTTTCCTCCGT 16 1100

TABLE 15 Inhibition of HSD17B13 RNA by 3-10-3 cEtgapmers targeting SEQ ID NO: 1, and 2 SEQ SEQ ID SEQ ID SEQ NO: 1 ID NO:NO: 2 ID NO: HSD17B13 SEQ Compound Start 1 Stop Start 2 Stop (% IDNumber Site Site Site Site Sequence (5′ to 3′) Inhibition) NO 1245082 1833 3112 3127 TCCTTGTGTAGTCCTA 61 1101 1245108 93 108 3187 3202TGATGGTGATCAGAAG 0 1102 1245134 125 140 3219 3234 AAACTTCACCAACGAC 271103 1245160 217 232 3311 3326 AATTCATAAGTAGTCT 28 1104 1245186 277 2927566 7581 GTTTCCTCCACACCGC 45 1105 1245212 324 339 7613 7628CCACATACGCATGCGC 68 1106 1245238 373 388 N/A N/A TTCACCTGATTTAGAG 9 11071245264 419 434 8813 8828 TGTCCCAGCATTATTC 31 1108 1245290 446 461 88408855 GGTGCTGAGAAGATCG 33 1109 1245316 490 505 8884 8899 CCTAGGATGTTGACCT3 1110 1245342 536 551 10422 10437 TCTCTCCATCATCGAT 24 1111 1245368 596611 10482 10497 GAGGTAAGGAATCCCT 27 1112 1245394 651 666 12069 12084ATGTCAGACCTCTGTG 19 1113 1245420 726 741 12144 12159 TGAACCCAGTATTCAC 101114 1245446 778 793 15659 15674 ACGACTTCATCTGTCT 8 1115 1245472 806 82115687 15702 GGTAAGTATTCCATCT 12 1116 1245498* 895 910 20710 20725TTTAAAATCGCTGAGG 24 1117 1245524* 937 952 20752 20767 TTGTGGCCAACCACTG83 1118 1245550* 988 1003 20803 20818 TATCATGCATACATCT 45 1119 12455761076 1091 20891 20906 AGTGCCAAACCAATGT 62 1120 1245602 1154 1169 2096920984 CAGACCTATGAAAAAC 26 1121 1245628 1296 1311 21111 21126GTGTAAATAAGTTCTC 61 1122 1245654 1328 1343 21143 21158 GAATGCTACTTGAACA44 1123 1245680 1356 1371 21171 21186 TGATATTCTGTGGCAT 69 1124 12457061405 1420 21220 21235 GCCTGCTGAAACTTGA 18 1125 1245732 1483 1498 2129821313 GGGCTAATGAAAAAGG 14 1126 1245758 1520 1535 21335 21350TCAAGTAATAAAGTCC 49 1127 1245784 1572 1587 21387 21402 AAATATAGAGGGTCCA0 1128 1245810 1631 1646 21446 21461 ATTTAAAATAGAGTCG 24 1129 12458361738 1753 21553 21568 TAATTTTTGAGCCTAA 41 1130 1245841 1765 1780 2158021595 GTACAGTTCCTTTTCC 55 38 1245862 1794 1809 21609 21624TGGGTCCATTGTTTCT 35 1131 1245888 2191 2206 22006 22021 GTCTTGATGTAGTGGG67 1132 1245914 2353 2368 22168 22183 ATAACTACAAGAGGTT 64 1133 1245940N/A N/A 3508 3523 TAACTAACCTGACACA 57 1134 1245966 N/A N/A 3675 3690CCCTAAGTTATTATCC 25 1135 1245992 N/A N/A 4361 4376 TATACATCAACTCCTC 391136 1246018 N/A N/A 4652 4667 AGTCATTTTTAATACG 13 1137 1246044 N/A N/A5168 5183 TTGCATAAGAGCCAAA 46 1138 1246065 N/A N/A 5659 5674ATAAGTTACCAGAGCA 75 48 1246070 N/A N/A 5736 5751 TAGTTGGTAGCTTGCT 661139 1246096 N/A N/A 5918 5933 ACCTTGAATGAGTGGT 26 1140 1246122 N/A N/A6185 6200 GCAATTTACTTTCAGC 66 1141 1246148 N/A N/A 6441 6456TCTAAACTAGTGGTAA 24 1142 1246174 N/A N/A 6743 6758 TTGCAATGAGATTACC 291143 1246200 N/A N/A 7787 7802 GACATAACTACTTCAG 66 1144 1246226 N/A N/A8133 8148 TTTGTTAGAGTGCTTA 80 1145 1246252 N/A N/A 8596 8611CATAAAGGTGGGATAA 23 1146 1246278 N/A N/A 8945 8960 GTATCTTAAGAGAAGG 301147 1246304 N/A N/A 9208 9223 AAAGATGTACACTGAC 57 1148 1246330 N/A N/A9431 9446 CTAACCAATTATATGA 21 1149 1246356 N/A N/A 9648 9663AATGTATGAGGTCTCC 65 1150 1246382 N/A N/A 9926 9941 GATTGAATTCACTATC 01151 1246408 N/A N/A 10064 10079 CCTTATGATAATTTGG 29 1152 1246434 N/AN/A 10390 10405 TGATCTTAAGGATCAT 0 1153 1246460 N/A N/A 11030 11045CATTCTAAACTACTAT 11 1154 1246486 N/A N/A 11542 11557 GACAATGGTTGCCACT 631155 1246512 N/A N/A 11858 11873 GATTAAGCAGAATTGT 37 1156 1246538 N/AN/A 12209 12224 CAATTTATCATACCAC 37 1157 1246564 N/A N/A 12513 12528ACAAGAGTTCTTGCAG 29 1158 1246590 N/A N/A 12693 12708 TTCGAATCATTAAGCT 631159 1246616 N/A N/A 12862 12877 CACCATGAAGGACTCC 48 1160 1246642 N/AN/A 13770 13785 TGCAATAGTACTATAG 24 1161 1246668 N/A N/A 13975 13990ATTTAGCATTGCCTGT 10 1162 1246694 N/A N/A 14128 14143 TAAATTACTCCGTTCT 361163 1246720 N/A N/A 14362 14377 GTGCAAGATGATGACA 19 1164 1246746 N/AN/A 14541 14556 GTATTTGAGATTCACC 41 1165 1246772 N/A N/A 15244 15259GCTAAGTATACTTTCT 37 1166 1246798 N/A N/A 15360 15375 GATGGTAAGGAGTAGT 281167 1246824 N/A N/A 15496 15511 CTGCATTAATGCCACC 67 1168 1246850 N/AN/A 16272 16287 CAAAGTTTGGGCAGAG 44 1169 1246876 N/A N/A 17046 17061AAAAAGCTTATCGAGT 8 1170 1246902 N/A N/A 17991 18006 GTTAGTATAGTTATCT 661171 1246928 N/A N/A 18671 18686 TTTACTGGGATACTAT 25 1172 1246954 N/AN/A 18901 18916 AGGGAAGATCTGGCTG 4 1173 1246980 N/A N/A 19563 19578AGCTATTGTCTTTGAT 39 1174 1247006 N/A N/A 19760 19775 CTCTTATCTGATATGA 71175 1247032 N/A N/A 20037 20052 GCATTAAAACTCTCAT 35 1176 1247058 N/AN/A 20376 20391 CAAGTAAGGTAAAGTC 33 1177 1247084 N/A N/A 20572 20587GTTTAACTTTCCTCCG 30 1178

TABLE 16Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2  HSD17B13 SEQCompound Start Stop Start Stop (% ID Number Site Site Site SiteSequence (5′ to 3′) Inhibition) NO 1245083   19   34  3113  3128GTCCTTGTGTAGTCCT 62 1179 1245109   98  113  3192  3207 GTAGATGATGGTGATC36 1180 1245135  126  141  3220  3235 AAAACTTCACCAACGA 29 1181 1245161 240  255  3334  3349 CCAATATGCTCTGTCG 65 1182 1245187  278  293  7567 7582 AGTTTCCTCCACACCG 28 1183 1245213  325  340  7614  7629ACCACATACGCATGCG 45 1184 1245239  374  389 N/A N/A CTTCACCTGATTTAGA  71185 1245265  421  436  8815  8830 ACTGTCCCAGCATTAT 40 1186 1245291  452 467  8846  8861 ATCCTTGGTGCTGAGA 13 1187 1245317  491  506  8885  8900TCCTAGGATGTTGACC  0 1188 1245343  537  552 10423 10438 TTCTCTCCATCATCGA35 1189 1245369  597  612 10483 10498 TGAGGTAAGGAATCCC  2 1190 1245395 652  667 12070 12085 GATGTCAGACCTCTGT  6 1191 1245421  727  742 1214512160 GTGAACCCAGTATTCA  1 1192 1245447  779  794 15660 15675TACGACTTCATCTGTC 29 1193 1245473  807  822 15688 15703 TGGTAAGTATTCCATC26 1194 1245499*  896  911 20711 20726 ATTTAAAATCGCTGAG 30 1195 1245525* 938  953 20753 20768 TTTGTGGCCAACCACT 88 1196 1245551*  989 1004 2080420819 TTATCATGCATACATC 52 1197 1245577 1077 1092 20892 20907TAGTGCCAAACCAATG 46 1198 1245603 1180 1195 20995 21010 GTTTTTAAGAGGCATG63 1199 1245629 1298 1313 21113 21128 CTGTGTAAATAAGTTC 38 1200 12456551329 1344 21144 21159 GGAATGCTACTTGAAC 63 1201 1245681 1357 1372 2117221187 TTGATATTCTGTGGCA 87 1202 1245707 1406 1421 21221 21236TGCCTGCTGAAACTTG 31 1203 1245733 1488 1503 21303 21318 GTTTTGGGCTAATGAA54 1204 1245759 1538 1553 21353 21368 GTTATACAGAAGACAG 54 1205 12457851573 1588 21388 21403 GAAATATAGAGGGTCC 22 1206 1245811 1654 1669 2146921484 GGGCTAGAACTTAAAA 35 1207 1245837 1742 1757 21557 21572GCTTTAATTTTTGAGC 26 1208 1245863 1795 1810 21610 21625 TTGGGTCCATTGTTTC44 1209 1245889 2192 2207 22007 22022 AGTCTTGATGTAGTGG 63 1210 12459152354 2369 22169 22184 TATAACTACAAGAGGT 46 1211 1245941 N/A N/A  3509 3524 CTAACTAACCTGACAC 23 1212 1245967 N/A N/A  3703  3718TAATTTTCAGATCCCG 75 1213 1245993 N/A N/A  4362  4377 ATATACATCAACTCCT 431214 1246019 N/A N/A  4991  5006 GAATTTTTGAGGTTGG 77 1215 1246045 N/AN/A  5173  5188 TTAGATTGCATAAGAG 61 1216 1246071 N/A N/A  5738  5753TTTAGTTGGTAGCTTG 63 1217 1246097 N/A N/A  5919  5934 AACCTTGAATGAGTGG 501218 1246123 N/A N/A  6204  6219 CATAGGACATGGAGAC 69 1219 1246149 N/AN/A  6443  6458 ATTCTAAACTAGTGGT 39 1220 1246175 N/A N/A  6784  6799CTCCTTATTTGTTAGA 26 1221 1246201 N/A N/A  7788  7803 TGACATAACTACTTCA 221222 1246227 N/A N/A  8137  8152 AAAGTTTGTTAGAGTG 75 1223 1246253 N/AN/A  8597  8612 TCATAAAGGTGGGATA 40 1224 1246279 N/A N/A  8959  8974GTTATAAGTTTCATGT 21 1225 1246305 N/A N/A  9215  9230 GCATTGAAAAGATGTA  01226 1246331 N/A N/A  9476  9491 TCTATACAAAGGCAGT 53 1227 1246357 N/AN/A  9649  9664 TAATGTATGAGGTCTC 51 1228 1246383 N/A N/A  9928  9943ATGATTGAATTCACTA 33 1229 1246409 N/A N/A 10112 10127 TAAACAATATTAAGGG  01230 1246435 N/A N/A 10494 10509 CCAATATGGGATGAGG 60 1231 1246461 N/AN/A 11074 11089 TTACAACCTGGTTTCA 25 1232 1246487 N/A N/A 11543 11558TGACAATGGTTGCCAC 40 1233 1246513 N/A N/A 11859 11874 TGATTAAGCAGAATTG 571234 1246539 N/A N/A 12210 12225 TCAATTTATCATACCA 26 1235 1246565 N/AN/A 12514 12529 GACAAGAGTTCTTGCA 22 1236 1246591 N/A N/A 12694 12709TTTCGAATCATTAAGC 30 1237 1246617 N/A N/A 12875 12890 ACCTATGGTCTAACAC 141238 1246643 N/A N/A 13771 13786 TTGCAATAGTACTATA  3 1239 1246669 N/AN/A 13976 13991 TATTTAGCATTGCCTG 12 1240 1246695 N/A N/A 14129 14144CTAAATTACTCCGTTC 20 1241 1246721 N/A N/A 14377 14392 TAGAATTGTCTGTTAG  91242 1246747 N/A N/A 14542 14557 CGTATTTGAGATTCAC 59 1243 1246773 N/AN/A 15245 15260 AGCTAAGTATACTTTC 18 1244 1246799 N/A N/A 15361 15376AGATGGTAAGGAGTAG 26 1245 1246825 N/A N/A 15511 15526 ATATTCCAGGATTTGC 261246 1246851 N/A N/A 16273 16288 GCAAAGTTTGGGCAGA 50 1247 1246877 N/AN/A 17047 17062 AAAAAAGCTTATCGAG  7 1248 1246903 N/A N/A 17992 18007AGTTAGTATAGTTATC 74 1249 1246929 N/A N/A 18695 18710 AAAGACTTTGAGACTC 681250 1246955 N/A N/A 18925 18940 GAAAGATGGAATGAGC 54 1251 1246981 N/AN/A 19588 19603 AGGTAAACTAAAGTAC  6 1252 1247007 N/A N/A 19778 19793CATACCACTCTTCTCA 24 1253 1247033 N/A N/A 20039 20054 ATGCATTAAAACTCTC 121254 1247059 N/A N/A 20377 20392 ACAAGTAAGGTAAAGT 38 1255 1247085 N/AN/A 20589 20604 AGAGTTATCTGGTTTG 56 1256

TABLE 17Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2  HSD17B13 SEQCompound Start Stop Start Stop (% ID Number Site Site Site SiteSequence (5′ to 3′) Inhibition) NO 1245084   20   35  3114  3129AGTCCTTGTGTAGTCC 64 1257 1245110  100  115  3194  3209 GAGTAGATGATGGTGA28 1258 1245136  127  142  3221  3236 AAAAACTTCACCAACG  8 1259 1245162 241  256  3335  3350 ACCAATATGCTCTGTC 67 1260 1245188  289  304  7578 7593 CACTCAGCTGCAGTTT 13 1261 1245214  326  341  7615  7630TACCACATACGCATGC 33 1262 1245240  375  390 N/A N/A TCTTCACCTGATTTAG 241263 1245266  422  437  8816  8831 TACTGTCCCAGCATTA 21 1264 1245292  453 468  8847  8862 CATCCTTGGTGCTGAG 12 1265 1245318  492  507  8886  8901GTCCTAGGATGTTGAC  1 1266 1245344  538  553 10424 10439 TTTCTCTCCATCATCG27 1267 1245370  598  613 10484 10499 ATGAGGTAAGGAATCC  0 1268 1245396 654  669 12072 12087 CTGATGTCAGACCTCT 35 1269 1245422  728  743 1214612161 GGTGAACCCAGTATTC  7 1270 1245448  780  795 15661 15676TTACGACTTCATCTGT 36 1271 1245474  810  825 15691 15706 TATTGGTAAGTATTCC67 1272 1245500*  897  912 20712 20727 GATTTAAAATCGCTGA 49 1273 1245526* 939  954 20754 20769 TTTTGTGGCCAACCAC 77 1274 1245552*  992 1007 2080720822 TCATTATCATGCATAC 67 1275 1245578 1078 1093 20893 20908CTAGTGCCAAACCAAT 49 1276 1245604 1183 1198 20998 21013 GAAGTTTTTAAGAGGC64 1277 1245630 1299 1314 21114 21129 CCTGTGTAAATAAGTT 18 1278 12456561331 1346 21146 21161 TTGGAATGCTACTTGA 72 1279 1245682 1358 1373 2117321188 GTTGATATTCTGTGGC 80 1280 1245708 1408 1423 21223 21238GCTGCCTGCTGAAACT 38 1281 1245734 1489 1504 21304 21319 CGTTTTGGGCTAATGA48 1282 1245760 1540 1555 21355 21370 GAGTTATACAGAAGAC 61 1283 12457861574 1589 21389 21404 GGAAATATAGAGGGTC 50 1284 1245812 1668 1683 2148321498 AAAAGGTTATCATGGG 49 1285 1245838 1750 1765 21565 21580CTGTGTTAGCTTTAAT 67 1286 1245841 1765 1780 21580 21595 GTACAGTTCCTTTTCC61   38 1245864 1796 1811 21611 21626 CTTGGGTCCATTGTTT 44 1287 12458902193 2208 22008 22023 TAGTCTTGATGTAGTG 55 1288 1245916 2355 2370 2217022185 TTATAACTACAAGAGG 68 1289 1245942 N/A N/A  3511  3526ATCTAACTAACCTGAC  0 1290 1245968 N/A N/A  3704  3719 GTAATTTTCAGATCCC 821291 1245994 N/A N/A  4363  4378 TATATACATCAACTCC 61 1292 1246020 N/AN/A  5029  5044 GCTTAAATGTTTAACC 67 1293 1246046 N/A N/A  5175  5190GTTTAGATTGCATAAG 46 1294 1246065 N/A N/A  5659  5674 ATAAGTTACCAGAGCA 88  48 1246072 N/A N/A  5739  5754 ATTTAGTTGGTAGCTT 35 1295 1246098 N/AN/A  5920  5935 AAACCTTGAATGAGTG 37 1296 1246124 N/A N/A  6205  6220CCATAGGACATGGAGA 68 1297 1246150 N/A N/A  6444  6459 AATTCTAAACTAGTGG 311298 1246176 N/A N/A  6795  6810 TAAAAATTGGCCTCCT 29 1299  7104  71191246202 N/A N/A  7804  7819 ATATATCCTTCCTTGG 20 1300 1246228 N/A N/A 8139  8154 GTAAAGTTTGTTAGAG 54 1301 1246254 N/A N/A  8598  8613GTCATAAAGGTGGGAT 28 1302 1246280 N/A N/A  8960  8975 CGTTATAAGTTTCATG 331303 1246306 N/A N/A  9256  9271 AATCATGGTGTGGAGG 11 1304 1246332 N/AN/A  9497  9512 GGAAGATTAATCATAA 32 1305 1246358 N/A N/A  9650  9665CTAATGTATGAGGTCT 46 1306 1246384 N/A N/A  9937  9952 TAATGAATCATGATTG  21307 1246410 N/A N/A 10145 10160 GAATCAAATAGATCCT 46 1308 1246436 N/AN/A 10495 10510 ACCAATATGGGATGAG 24 1309 1246462 N/A N/A 11078 11093ATAATTACAACCTGGT 44 1310 1246488 N/A N/A 11547 11562 CTCTTGACAATGGTTG 501311 11572 11587 1246514 N/A N/A 11861 11876 CATGATTAAGCAGAAT 42 13121246540 N/A N/A 12211 12226 ATCAATTTATCATACC 11 1313 1246566 N/A N/A12515 12530 AGACAAGAGTTCTTGC 30 1314 1246592 N/A N/A 12701 12716AAATTGGTTTCGAATC 32 1315 1246618 N/A N/A 12889 12904 CTTTAGTCAACAGTAC 121316 1246644 N/A N/A 13783 13798 AACAATCAGGAGTTGC 31 1317 1246670 N/AN/A 13997 14012 CTCTATAAAATCAATC  0 1318 1246696 N/A N/A 14130 14145TCTAAATTACTCCGTT 15 1319 1246722 N/A N/A 14378 14393 GTAGAATTGTCTGTTA 511320 1246748 N/A N/A 14556 14571 TCCGGTAAGAATTTCG 63 1321 1246774 N/AN/A 15246 15261 TAGCTAAGTATACTTT 10 1322 1246800 N/A N/A 15364 15379ATTAGATGGTAAGGAG  4 1323 1246826 N/A N/A 15570 15585 GTAAATGATGGCAGGA 341324 1246852 N/A N/A 16274 16289 AGCAAAGTTTGGGCAG 44 1325 1246878 N/AN/A 17077 17092 AAATTAGAGGCCCAGG 43 1326 1246904 N/A N/A 17994 18009GAAGTTAGTATAGTTA 59 1327 1246930 N/A N/A 18732 18747 CTAGTTACAAACCACC 431328 1246956 N/A N/A 18958 18973 AGATTTACTTCCTTGT 41 1329 1246982 N/AN/A 19590 19605 TAAGGTAAACTAAAGT  9 1330 1247008 N/A N/A 19781 19796ATACATACCACTCTTC 18 1331 1247034 N/A N/A 20087 20102 AGTAACTTTATTAACG 121332 1247060 N/A N/A 20381 20396 AATCACAAGTAAGGTA 52 1333 1247086 N/AN/A 20599 20614 GAATACGCTGAGAGTT 11 1334

TABLE 18Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2  HSD17B13 SEQCompound Start Stop Start Stop (% ID Number Site Site Site SiteSequence (5′ to 3′) Inhibition) NO 1245085   21   36  3115  3130CAGTCCTTGTGTAGTC 70 1335 1245111  101  116  3195  3210 GGAGTAGATGATGGTG31 1336 1245137  154  169  3248  3263 GCCACAGATTTTCTCC 49 1337 1245163 242  257  3336  3351 AACCAATATGCTCTGT 51 1338 1245189  290  305  7579 7594 GCACTCAGCTGCAGTT 29 1339 1245215  327  342  7616  7631CTACCACATACGCATG 25 1340 1245241  392  407  8786  8801 TACATCACCCACTTCT37 1341 1245267  423  438  8817  8832 ATACTGTCCCAGCATT 32 1342 1245293 454  469  8848  8863 TCATCCTTGGTGCTGA 12 1343 1245319  493  508  8887 8902 TGTCCTAGGATGTTGA 41 1344 1245345  548  563 10434 10449GTGGCCATGATTTCTC 40 1345 1245371  599  614 10485 10500 GATGAGGTAAGGAATC 0 1346 1245397  655  670 12073 12088 TCTGATGTCAGACCTC 42 1347 1245423 729  744 12147 12162 TGGTGAACCCAGTATT  0 1348 1245449  781  796 1566215677 CTTACGACTTCATCTG 38 1349 1245475  812  827 15693 15708CTTATTGGTAAGTATT 22 1350 1245501*  898  913 20713 20728 CGATTTAAAATCGCTG40 1351 1245527*  940  955 20755 20770 ATTTTGTGGCCAACCA 59 1352 1245553 996 1011 20811 20826 CATATCATTATCATGC 66 1353 1245579 1079 1094 2089420909 GCTAGTGCCAAACCAA 70 1354 1245605 1192 1207 21007 21022GTAAGCACAGAAGTTT 55 1355 1245631 1300 1315 21115 21130 CCCTGTGTAAATAAGT41 1356 1245657 1332 1347 21147 21162 ATTGGAATGCTACTTG 53 1357 12456831359 1374 21174 21189 TGTTGATATTCTGTGG 68 1358 1245709 1412 1427 2122721242 TAAAGCTGCCTGCTGA 44 1359 1245735 1490 1505 21305 21320CCGTTTTGGGCTAATG 58 1360 1245761 1545 1560 21360 21375 CTTCAGAGTTATACAG35 1361 1245787 1575 1590 21390 21405 AGGAAATATAGAGGGT 54 1362 12458131670 1685 21485 21500 GAAAAAGGTTATCATG 31 1363 1245839 1751 1766 2156621581 CCTGTGTTAGCTTTAA 67 1364 1245841 1765 1780 21580 21595GTACAGTTCCTTTTCC 58   38 1245865 1797 1812 21612 21627 TCTTGGGTCCATTGTT60 1365 1245891 2194 2209 22009 22024 TTAGTCTTGATGTAGT 61 1366 12459172378 2393 22193 22208 GTTTAGAAGTCAAACG  0 1367 1245943 N/A N/A  3512 3527 CATCTAACTAACCTGA  0 1368 1245969 N/A N/A  3750  3765TAAAGGTTTCTGTTGC 66 1369 1245995 N/A N/A  4405  4420 ATTCGAATTTCTTCAA 651370 1246021 N/A N/A  5042  5057 GAATCATTCAGTAGCT 65 1371 1246047 N/AN/A  5177  5192 CAGTTTAGATTGCATA 60 1372 1246065 N/A N/A  5659  5674ATAAGTTACCAGAGCA 85   48 1246073 N/A N/A  5740  5755 GATTTAGTTGGTAGCT 631373 1246099 N/A N/A  5921  5936 CAAACCTTGAATGAGT 53 1374 1246125 N/AN/A  6206  6221 ACCATAGGACATGGAG 62 1375 1246151 N/A N/A  6445  6460TAATTCTAAACTAGTG 11 1376 1246177 N/A N/A  6796  6811 ATAAAAATTGGCCTCC 411377 1246203 N/A N/A  7828  7843 TGGATTACATACAAGA 68 1378 1246229 N/AN/A  8140  8155 TGTAAAGTTTGTTAGA 35 1379 1246255 N/A N/A  8599  8614TGTCATAAAGGTGGGA 48 1380 1246281 N/A N/A  8961  8976 CCGTTATAAGTTTCAT 541381 1246307 N/A N/A  9257  9272 AAATCATGGTGTGGAG  1 1382 1246333 N/AN/A  9499  9514 CTGGAAGATTAATCAT 31 1383 1246359 N/A N/A  9652  9667AGCTAATGTATGAGGT 56 1384 1246385 N/A N/A  9938  9953 CTAATGAATCATGATT 201385 1246411 N/A N/A 10180 10195 CTAATCTCAGTACTCC 53 1386 1246437 N/AN/A 10496 10511 TACCAATATGGGATGA  1 1387 1246463 N/A N/A 11079 11094TATAATTACAACCTGG 46 1388 1246489 N/A N/A 11548 11563 TCTCTTGACAATGGTT 701389 11573 11588 1246515 N/A N/A 11865 11880 CTTACATGATTAAGCA 44 13901246541 N/A N/A 12238 12253 GCCTAAACATTTCTCA  2 1391 1246567 N/A N/A12516 12531 GAGACAAGAGTTCTTG 19 1392 1246593 N/A N/A 12703 12718AAAAATTGGTTTCGAA 13 1393 1246619 N/A N/A 13551 13566 CTCTCTAAAGGGCTGC 551394 1246645 N/A N/A 13813 13828 TTTTATTGGGCCCAAT 18 1395 1246671 N/AN/A 14007 14022 ATCTAGCAACCTCTAT 12 1396 1246697 N/A N/A 14131 14146TTCTAAATTACTCCGT 53 1397 1246723 N/A N/A 14380 14395 GTGTAGAATTGTCTGT 421398 1246749 N/A N/A 14557 14572 TTCCGGTAAGAATTTC 33 1399 1246775 N/AN/A 15248 15263 TATAGCTAAGTATACT 23 1400 1246801 N/A N/A 15365 15380CATTAGATGGTAAGGA 32 1401 1246827 N/A N/A 15571 15586 AGTAAATGATGGCAGG 401402 1246853 N/A N/A 16287 16302 TAGAATAGTCTTCAGC 70 1403 1246879 N/AN/A 17135 17150 AATAGCCATGTAGCTA 28 1404 1246905 N/A N/A 17995 18010TGAAGTTAGTATAGTT 43 1405 1246931 N/A N/A 18733 18748 CCTAGTTACAAACCAC 511406 1246957 N/A N/A 18962 18977 TGCAAGATTTACTTCC 45 1407 1246983 N/AN/A 19598 19613 CTCTATAATAAGGTAA  0 1408 1247009 N/A N/A 19782 19797GATACATACCACTCTT 52 1409 1247035 N/A N/A 20110 20125 CAAGACATTCTAGCCT 581410 1247061 N/A N/A 20383 20398 GTAATCACAAGTAAGG 70 1411 1247087 N/AN/A 20600 20615 AGAATACGCTGAGAGT 56 1412

TABLE 19Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2  HSD17B13 SEQCompound Start Stop Start Stop (% ID Number Site Site Site SiteSequence (5′ to 3′) Inhibition) NO 1245086   22   37  3116  3131TCAGTCCTTGTGTAGT 72 1413 1245112  103  118  3197  3212 TAGGAGTAGATGATGG15 1414 1245138  166  181  3260  3275 ACAATCTCCCCAGCCA 67 1415 1245164 243  258  3337  3352 GAACCAATATGCTCTG 61 1416 1245190  291  306  7580 7595 GGCACTCAGCTGCAGT 49 1417 1245216  328  343  7617  7632TCTACCACATACGCAT 55 1418 1245242  393  408  8787  8802 TTACATCACCCACTTC37 1419 1245268  424  439  8818  8833 TATACTGTCCCAGCAT 40 1420 1245294 456  471  8850  8865 CTTCATCCTTGGTGCT 30 1421 1245320  494  509  8888 8903 ATGTCCTAGGATGTTG 50 1422 1245346  551  566 10437 10452GATGTGGCCATGATTT  9 1423 1245372  606  621 10492 10507 AATATGGGATGAGGTA53 1424 1245398  656  671 12074 12089 TTCTGATGTCAGACCT 42 1425 1245424 730  745 12148 12163 TTGGTGAACCCAGTAT 31 1426 1245450  782  797 1566315678 TCTTACGACTTCATCT 34 1427 1245476  813  828 15694 15709TCTTATTGGTAAGTAT 25 1428 1245502*  899  914 20714 20729 ACGATTTAAAATCGCT44 1429 1245528*  941  956 20756 20771 GATTTTGTGGCCAACC 91 1430 12455541006 1021 20821 20836 CGAAACTATTCATATC 66 1431 1245580 1080 1095 2089520910 TGCTAGTGCCAAACCA 78 1432 1245606 1198 1213 21013 21028GTTTATGTAAGCACAG 67 1433 1245632 1301 1316 21116 21131 TCCCTGTGTAAATAAG35 1434 1245658 1333 1348 21148 21163 GATTGGAATGCTACTT 58 1435 12456841364 1379 21179 21194 GTTCTTGTTGATATTC 84 1436 1245710 1414 1429 2122921244 GATAAAGCTGCCTGCT 42 1437 1245736 1491 1506 21306 21321ACCGTTTTGGGCTAAT 78 1438 1245762 1547 1562 21362 21377 GACTTCAGAGTTATAC16 1439 1245788 1589 1604 21404 21419 GACTATAAAAAGGGAG 40 1440 12458141702 1717 21517 21532 GACCAAGGATATATGA 48 1441 1245840 1752 1767 2156721582 TCCTGTGTTAGCTTTA 56 1442 1245841 1765 1780 21580 21595GTACAGTTCCTTTTCC 57   38 1245866 1798 1813 21613 21628 CTCTTGGGTCCATTGT40 1443 1245892 2195 2210 22010 22025 ATTAGTCTTGATGTAG 67 1444 12459182379 2394 22194 22209 AGTTTAGAAGTCAAAC 23 1445 1245944 N/A N/A  3530 3545 TCTTAATTACATTCCC 64 1446 1245970 N/A N/A  3751  3766CTAAAGGTTTCTGTTG 34 1447 1245996 N/A N/A  4406  4421 CATTCGAATTTCTTCA 771448 1246022 N/A N/A  5045  5060 AGTGAATCATTCAGTA 86 1449 1246048 N/AN/A  5178  5193 ACAGTTTAGATTGCAT 84 1450 1246065 N/A N/A  5659  5674ATAAGTTACCAGAGCA 82   48 1246074 N/A N/A  5741  5756 TGATTTAGTTGGTAGC 791451 1246100 N/A N/A  5923  5938 GGCAAACCTTGAATGA 61 1452 1246126 N/AN/A  6207  6222 AACCATAGGACATGGA 71 1453 1246152 N/A N/A  6446  6461GTAATTCTAAACTAGT 39 1454 1246178 N/A N/A  6914  6929 CTCGGGAAGTTTAGAC 471455 1246204 N/A N/A  7829  7844 GTGGATTACATACAAG 57 1456 1246230 N/AN/A  8141  8156 ATGTAAAGTTTGTTAG 12 1457 1246256 N/A N/A  8610  8625CAAGGGAACACTGTCA 58 1458 1246282 N/A N/A  8962  8977 TCCGTTATAAGTTTCA 651459 1246308 N/A N/A  9260  9275 ACAAAATCATGGTGTG 26 1460 1246334 N/AN/A  9510  9525 ATATTGAGGCACTGGA 53 1461 1246360 N/A N/A  9653  9668TAGCTAATGTATGAGG 48 1462 1246386 N/A N/A  9939  9954 ACTAATGAATCATGAT 391463 1246412 N/A N/A 10181 10196 ACTAATCTCAGTACTC 45 1464 1246438 N/AN/A 10498 10513 CTTACCAATATGGGAT 11 1465 1246464 N/A N/A 11155 11170TGGAAACATGCTTGGC 62 1466 1246490 N/A N/A 11549 11564 TTCTCTTGACAATGGT 671467 11574 11589 1246516 N/A N/A 11892 11907 GTATAAATGGCAATTC 56 14681246542 N/A N/A 12251 12266 TATTAGTTGGCCTGCC 14 1469 1246568 N/A N/A12598 12613 TCTTATCCACACCTTC 31 1470 1246594 N/A N/A 12704 12719AAAAAATTGGTTTCGA 20 1471 1246620 N/A N/A 13574 13589 CTATCAGAACAGTTCA 481472 1246646 N/A N/A 13814 13829 TTTTTATTGGGCCCAA 51 1473 1246672 N/AN/A 14008 14023 AATCTAGCAACCTCTA 22 1474 1246698 N/A N/A 14132 14147TTTCTAAATTACTCCG 54 1475 1246724 N/A N/A 14382 14397 TAGTGTAGAATTGTCT 461476 1246750 N/A N/A 14600 14615 AGAAATCTAAGAACCC 25 1477 1246776 N/AN/A 15252 15267 ATTCTATAGCTAAGTA 23 1478 1246802 N/A N/A 15366 15381GCATTAGATGGTAAGG 64 1479 1246828 N/A N/A 15633 15648 CCATAATCTGTGATTA  91480 1246854 N/A N/A 16289 16304 GTTAGAATAGTCTTCA 46 1481 1246880 N/AN/A 17136 17151 GAATAGCCATGTAGCT 21 1482 1246906 N/A N/A 17996 18011ATGAAGTTAGTATAGT 55 1483 1246932 N/A N/A 18734 18749 GCCTAGTTACAAACCA 561484 1246958 N/A N/A 18968 18983 GACTAATGCAAGATTT 55 1485 1246984 N/AN/A 19599 19614 ACTCTATAATAAGGTA 42 1486 1247010 N/A N/A 19785 19800ACTGATACATACCACT 52 1487 1247036 N/A N/A 20112 20127 ATCAAGACATTCTAGC 611488 1247062 N/A N/A 20385 20400 TAGTAATCACAAGTAA 30 1489 1247088 N/AN/A 20601 20616 TAGAATACGCTGAGAG 47 1490

TABLE 20Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2  HSD17B13 SEQCompound Start Stop Start Stop (% ID Number Site Site Site SiteSequence (5′ to 3′) Inhibition) NO 1245087   23   38  3117  3132TTCAGTCCTTGTGTAG 45 1491 1245113  104  119  3198  3213 GTAGGAGTAGATGATG 7 1492 1245139  167  182  3261  3276 AACAATCTCCCCAGCC 59 1493 1245165 244  259  3338  3353 AGAACCAATATGCTCT 38 1494 1245191  292  307  7581 7596 CGGCACTCAGCTGCAG 55 1495 1245217  329  344  7618  7633GTCTACCACATACGCA 66 1496 1245243  394  409  8788  8803 GTTACATCACCCACTT41 1497 1245269  425  440  8819  8834 ATATACTGTCCCAGCA 43 1498 1245295 457  472  8851  8866 TCTTCATCCTTGGTGC 48 1499 1245321  495  510  8889 8904 AATGTCCTAGGATGTT 70 1500 1245347  552  567 10438 10453CGATGTGGCCATGATT 44 1501 1245373  607  622 10493 10508 CAATATGGGATGAGGT62 1502 1245399  657  672 12075 12090 GTTCTGATGTCAGACC 55 1503 1245425 731  746 12149 12164 TTTGGTGAACCCAGTA 34 1504 1245451  783  798 1566415679 TTCTTACGACTTCATC 47 1505 1245477  835  850 15716 15731TACGATGGAACAAAAA 20 1506 1245503*  900  915 20715 20730 TACGATTTAAAATCGC 0 1507 1245529*  942  957 20757 20772 TGATTTTGTGGCCAAC 72 1508 12455551007 1022 20822 20837 TCGAAACTATTCATAT 64 1509 1245581 1081 1096 2089620911 CTGCTAGTGCCAAACC 74 1510 1245607 1202 1217 21017 21032GTATGTTTATGTAAGC 80 1511 1245633 1305 1320 21120 21135 ACCTTCCCTGTGTAAA60 1512 1245659 1334 1349 21149 21164 AGATTGGAATGCTACT 63 1513 12456851366 1381 21181 21196 GTGTTCTTGTTGATAT 81 1514 1245711 1415 1430 2123021245 AGATAAAGCTGCCTGC 48 1515 1245737 1492 1507 21307 21322CACCGTTTTGGGCTAA 85 1516 1245763 1548 1563 21363 21378 GGACTTCAGAGTTATA36 1517 1245789 1599 1614 21414 21429 TATCTTATAAGACTAT 43 1518 12458151703 1718 21518 21533 GGACCAAGGATATATG 56 1519 1245841 1765 1780 2158021595 GTACAGTTCCTTTTCC 67   38 1245867 1799 1814 21614 21629TCTCTTGGGTCCATTG 63 1520 1245893 2196 2211 22011 22026 GATTAGTCTTGATGTA65 1521 1245919 N/A N/A  3356  3371 ACCTTATTAATATCCC 71 1522 1245945 N/AN/A  3532  3547 GTTCTTAATTACATTC 64 1523 1245971 N/A N/A  3753  3768CACTAAAGGTTTCTGT 56 1524 1245997 N/A N/A  4407  4422 TCATTCGAATTTCTTC 761525 1246023 N/A N/A  5046  5061 GAGTGAATCATTCAGT 87 1526 1246049 N/AN/A  5179  5194 AACAGTTTAGATTGCA 71 1527 1246075 N/A N/A  5742  5757CTGATTTAGTTGGTAG 78 1528 1246101 N/A N/A  5928  5943 TTTAGGGCAAACCTTG 671529 1246127 N/A N/A  6208  6223 TAACCATAGGACATGG 70 1530 1246153 N/AN/A  6447  6462 AGTAATTCTAAACTAG 31 1531 1246179 N/A N/A  7101  7116AAATTGGCCTCCTGGG 44 1532 1246205 N/A N/A  7846  7861 ATAATGGGCAGAGCTG 531533 1246231 N/A N/A  8165  8180 TTATTGTAGGGATTGA 63 1534 1246257 N/AN/A  8612  8627 GCCAAGGGAACACTGT 61 1535 1246283 N/A N/A  8975  8990GAAGTATGTGAACTCC 56 1536 1246309 N/A N/A  9312  9327 ATTACTTCTGATGTCC 651537 1246335 N/A N/A  9511  9526 AATATTGAGGCACTGG 54 1538 1246361 N/AN/A  9656  9671 AGGTAGCTAATGTATG 53 1539 1246387 N/A N/A  9940  9955CACTAATGAATCATGA 25 1540 1246413 N/A N/A 10182 10197 CACTAATCTCAGTACT 481541 1246439 N/A N/A 10501 10516 ATACTTACCAATATGG  0 1542 1246465 N/AN/A 11156 11171 ATGGAAACATGCTTGG 48 1543 1246491 N/A N/A 11565 11580CAATGGTTGATAGTTT 47 1544 1246517 N/A N/A 11894 11909 GAGTATAAATGGCAAT 531545 1246543 N/A N/A 12252 12267 CTATTAGTTGGCCTGC 32 1546 1246569 N/AN/A 12600 12615 GTTCTTATCCACACCT 57 1547 1246595 N/A N/A 12705 12720TAAAAAATTGGTTTCG 22 1548 1246621 N/A N/A 13575 13590 ACTATCAGAACAGTTC 621549 1246647 N/A N/A 13815 13830 GTTTTTATTGGGCCCA 67 1550 1246673 N/AN/A 14009 14024 CAATCTAGCAACCTCT 51 1551 1246699 N/A N/A 14166 14181AGCAAGCCAACAGAGA 40 1552 1246725 N/A N/A 14384 14399 CTTAGTGTAGAATTGT 561553 1246751 N/A N/A 14614 14629 AATTATTTCTTGCGAG 16 1554 1246777 N/AN/A 15253 15268 AATTCTATAGCTAAGT  9 1555 1246803 N/A N/A 15367 15382GGCATTAGATGGTAAG 62 1556 1246829 N/A N/A 15634 15649 GCCATAATCTGTGATT  01557 1246855 N/A N/A 16290 16305 AGTTAGAATAGTCTTC 67 1558 1246881 N/AN/A 17139 17154 ATTGAATAGCCATGTA 39 1559 1246907 N/A N/A 17997 18012TATGAAGTTAGTATAG 30 1560 1246933 N/A N/A 18746 18761 TATATACCTGTTGCCT 551561 1246959 N/A N/A 19388 19403 ATGAGTAGGCAACTGA 61 1562 1246985 N/AN/A 19608 19623 CTATTATGCACTCTAT 32 1563 1247011 N/A N/A 19786 19801CACTGATACATACCAC 64 1564 1247037 N/A N/A 20114 20129 GCATCAAGACATTCTA 721565 1247063 N/A N/A 20387 20402 TATAGTAATCACAAGT 53 1566 1247089 N/AN/A 20602 20617 TTAGAATACGCTGAGA 48 1567

TABLE 21Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2  HSD17B13 SEQCompound Start Stop Start Stop (% ID Number Site Site Site SiteSequence (5′ to 3′) Inhibition) NO 1245088   24   39  3118  3133GTTCAGTCCTTGTGTA 38 1568 1245114  105  120  3199  3214 AGTAGGAGTAGATGAT 0 1569 1245140  168  183  3262  3277 GAACAATCTCCCCAGC 63 1570 1245166 245  260  3339  3354 CAGAACCAATATGCTC 56 1571 1245192  293  308  7582 7597 TCGGCACTCAGCTGCA 52 1572 1245218  330  345  7619  7634AGTCTACCACATACGC 65 1573 1245244  395  410  8789  8804 TGTTACATCACCCACT35 1574 1245270  426  441  8820  8835 GATATACTGTCCCAGC 34 1575 1245296 458  473  8852  8867 CTCTTCATCCTTGGTG 25 1576 1245322  496  511  8890 8905 AAATGTCCTAGGATGT 36 1577 1245348  553  568 10439 10454ACGATGTGGCCATGAT 52 1578 1245374  608  623 N/A N/A ACAATATGGGATGAGG 711579 1245400  658  673 12076 12091 AGTTCTGATGTCAGAC 40 1580 1245426  749 764 N/A N/A TAATCTTGTGCTTGGA 54 1581 1245452  784  799 15665 15680CTTCTTACGACTTCAT 45 1582 1245478  836  851 15717 15732 ATACGATGGAACAAAA27 1583 1245504*  901  916 20716 20731 ATACGATTTAAAATCG 17 1584 1245530* 966  981 20781 20796 GGAGCTTATTTATTCA 38 1585 1245556 1008 1023 2082320838 TTCGAAACTATTCATA 44 1586 1245582 1082 1097 20897 20912GCTGCTAGTGCCAAAC 67 1587 1245608 1250 1265 21065 21080 GTCCACCTTTAAATGG33 1588 1245634 1306 1321 21121 21136 AACCTTCCCTGTGTAA 38 1589 12456601335 1350 21150 21165 CAGATTGGAATGCTAC 74 1590 1245686 1367 1382 2118221197 TGTGTTCTTGTTGATA 69 1591 1245712 1416 1431 21231 21246GAGATAAAGCTGCCTG 67 1592 1245738 1493 1508 21308 21323 GCACCGTTTTGGGCTA74 1593 1245764 1551 1566 21366 21381 GGTGGACTTCAGAGTT 26 1594 12457901600 1615 21415 21430 GTATCTTATAAGACTA 81 1595 1245816 1704 1719 2151921534 GGGACCAAGGATATAT 17 1596 1245841 1765 1780 21580 21595GTACAGTTCCTTTTCC 54   38 1245842 1766 1781 21581 21596 AGTACAGTTCCTTTTC69 1597 1245868 1800 1815 21615 21630 TTCTCTTGGGTCCATT 44 1598 12458942197 2212 22012 22027 AGATTAGTCTTGATGT 63 1599 1245920 N/A N/A N/A N/ACACCTTATTAATATCC 34 1600 1245946 N/A N/A  3537  3552 GCTTAGTTCTTAATTA 281601 1245972 N/A N/A  3754  3769 GCACTAAAGGTTTCTG 75 1602 1245998 N/AN/A  4408  4423 TTCATTCGAATTTCTT 71 1603 1246024 N/A N/A  5051  5066CCTTAGAGTGAATCAT 65 1604 1246050 N/A N/A  5180  5195 CAACAGTTTAGATTGC 661605 1246065 N/A N/A  5659  5674 ATAAGTTACCAGAGCA 91   48 1246076 N/AN/A  5743  5758 ACTGATTTAGTTGGTA 55 1606 1246102 N/A N/A  5929  5944ATTTAGGGCAAACCTT 35 1607 1246128 N/A N/A  6209  6224 ATAACCATAGGACATG 701608 1246154 N/A N/A  6453  6468 CTAAGTAGTAATTCTA 35 1609 1246180 N/AN/A  7103  7118 AAAAATTGGCCTCCTG 41 1610 1246206 N/A N/A  7847  7862AATAATGGGCAGAGCT 43 1611 1246232 N/A N/A  8166  8181 GTTATTGTAGGGATTG 691612 1246258 N/A N/A  8643  8658 CAAGACAGACTGTTGA 39 1613 1246284 N/AN/A  8976  8991 AGAAGTATGTGAACTC 41 1614 1246310 N/A N/A  9315  9330GTAATTACTTCTGATG 41 1615 1246336 N/A N/A  9512  9527 TAATATTGAGGCACTG 331616 1246362 N/A N/A  9659  9674 TATAGGTAGCTAATGT 31 1617 1246388 N/AN/A  9941  9956 ACACTAATGAATCATG  7 1618 1246414 N/A N/A 10183 10198ACACTAATCTCAGTAC  6 1619 1246440 N/A N/A 10502 10517 GATACTTACCAATATG 221620 1246466 N/A N/A 11210 11225 CTGTAGGTTTTGCTTC 27 1621 1246492 N/AN/A 11567 11582 GACAATGGTTGATAGT 67 1622 1246518 N/A N/A 11925 11940GCCAAAAATCAGCCAC 11 1623 1246544 N/A N/A 12253 12268 TCTATTAGTTGGCCTG 261624 1246570 N/A N/A 12609 12624 AATTTTCGGGTTCTTA 35 1625 1246596 N/AN/A 12710 12725 TCCAGTAAAAAATTGG 12 1626 1246622 N/A N/A 13577 13592CCACTATCAGAACAGT 31 1627 1246648 N/A N/A 13841 13856 ACGAAGCCTGAATGCC 521628 1246674 N/A N/A 14010 14025 ACAATCTAGCAACCTC 44 1629 1246700 N/AN/A 14167 14182 TAGCAAGCCAACAGAG 21 1630 1246726 N/A N/A 14390 14405CATAGGCTTAGTGTAG 38 1631 1246752 N/A N/A 14615 14630 GAATTATTTCTTGCGA 611632 1246778 N/A N/A 15279 15294 TCAAAGCCTGTTGGAT 35 1633 1246804 N/AN/A 15368 15383 AGGCATTAGATGGTAA 51 1634 1246830 N/A N/A 15750 15765TACTTACTTCTGTAGT 12 1635 1246856 N/A N/A 16291 16306 TAGTTAGAATAGTCTT 231636 1246882 N/A N/A 17143 17158 GTAAATTGAATAGCCA 55 1637 1246908 N/AN/A 17999 18014 CTTATGAAGTTAGTAT 43 1638 1246934 N/A N/A 18747 18762ATATATACCTGTTGCC 28 1639 1246960 N/A N/A 19389 19404 GATGAGTAGGCAACTG 421640 1246986 N/A N/A 19609 19624 TCTATTATGCACTCTA 55 1641 1247012 N/AN/A 19815 19830 GTTCAAATTGGATGCA 68 1642 1247038 N/A N/A 20124 20139TCTGATTACAGCATCA 48 1643 1247064 N/A N/A 20388 20403 CTATAGTAATCACAAG 351644 1247090 N/A N/A 20603 20618 TTTAGAATACGCTGAG 44 1645

TABLE 22Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2  HSD17B13 SEQCompound Start Stop Start Stop (% ID Number Site Site Site SiteSequence (5′ to 3′) Inhibition) NO 1245089   25   40  3119  3134GGTTCAGTCCTTGTGT 57 1646 1245115  106  121  3200  3215 AAGTAGGAGTAGATGA 0 1647 1245141  171  186  3265  3280 TGAGAACAATCTCCCC 69 1648 1245167 246  261  3340  3355 ACAGAACCAATATGCT 40 1649 1245193  294  309  7583 7598 TTCGGCACTCAGCTGC 41 1650 1245219  354  369  7643  7658GATAGATCTCTTCTCT  0 1651 1245245  396  411  8790  8805 TTGTTACATCACCCAC34 1652 1245271  427  442  8821  8836 GGATATACTGTCCCAG  9 1653 1245297 464  479  8858  8873 GGTAATCTCTTCATCC  9 1654 1245323  497  512  8891 8906 AAAATGTCCTAGGATG  0 1655 1245349  554  569 10440 10455GACGATGTGGCCATGA 42 1656 1245375  609  624 N/A N/A AACAATATGGGATGAG 391657 1245401  659  674 12077 12092 AAGTTCTGATGTCAGA  7 1658 1245427  750 765 N/A N/A ATAATCTTGTGCTTGG 36 1659 1245453  785  800 15666 15681ACTTCTTACGACTTCA 43 1660 1245479  837  852 15718 15733 TATACGATGGAACAAA 4 1661 1245505*  902  917 20717 20732 CATACGATTTAAAATC 13 1662 1245531* 967  982 20782 20797 TGGAGCTTATTTATTC 39 1663 1245557 1009 1024 2082420839 ATTCGAAACTATTCAT 24 1664 1245583 1083 1098 20898 20913TGCTGCTAGTGCCAAA 58 1665 1245609 1251 1266 21066 21081 TGTCCACCTTTAAATG29 1666 1245635 1307 1322 21122 21137 AAACCTTCCCTGTGTA 34 1667 12456611336 1351 21151 21166 ACAGATTGGAATGCTA 50 1668 1245687 1379 1394 2119421209 GTGCACTCATTCTGTG  6 1669 1245713 1418 1433 21233 21248TTGAGATAAAGCTGCC 49 1670 1245739 1494 1509 21309 21324 TGCACCGTTTTGGGCT36 1671 1245765 1552 1567 21367 21382 TGGTGGACTTCAGAGT 17 1672 12457911601 1616 21416 21431 TGTATCTTATAAGACT 45 1673 1245817 1705 1720 2152021535 TGGGACCAAGGATATA 20 1674 1245841 1765 1780 21580 21595GTACAGTTCCTTTTCC 48   38 1245843 1767 1782 21582 21597 CAGTACAGTTCCTTTT43 1675 1245869 1801 1816 21616 21631 CTTCTCTTGGGTCCAT 51 1676 12458952198 2213 22013 22028 AAGATTAGTCTTGATG 25 1677 1245921 N/A N/A N/A N/ATCACCTTATTAATATC  0 1678 1245947 N/A N/A  3546  3561 AAAATCGCTGCTTAGT 351679 1245973 N/A N/A  3755  3770 GGCACTAAAGGTTTCT 62 1680 1245999 N/AN/A  4409  4424 GTTCATTCGAATTTCT 76 1681 1246025 N/A N/A  5053  5068AGCCTTAGAGTGAATC 74 1682 1246051 N/A N/A  5187  5202 CCCAACGCAACAGTTT 661683 1246065 N/A N/A  5659  5674 ATAAGTTACCAGAGCA 84   48 1246077 N/AN/A  5759  5774 AATAGGAGAGTCTTTC 47 1684 1246103 N/A N/A  5930  5945TATTTAGGGCAAACCT 40 1685 1246129 N/A N/A  6210  6225 CATAACCATAGGACAT 411686 1246155 N/A N/A  6454  6469 GCTAAGTAGTAATTCT 57 1687 1246181 N/AN/A  7119  7134 GATTAGTTAACCTTTT 58 1688 1246207 N/A N/A  7848  7863TAATAATGGGCAGAGC 30 1689 1246233 N/A N/A  8171  8186 ACAGAGTTATTGTAGG 581690 1246259 N/A N/A  8670  8685 ATTGTATGAGGTCTCT 49 1691 1246285 N/AN/A  8977  8992 CAGAAGTATGTGAACT 22 1692 1246311 N/A N/A  9329  9344CTATATACATCCAAGT  6 1693 1246337 N/A N/A  9513  9528 CTAATATTGAGGCACT 511694 1246363 N/A N/A  9661  9676 GCTATAGGTAGCTAAT 20 1695 1246389 N/AN/A  9942  9957 CACACTAATGAATCAT 30 1696 1246415 N/A N/A 10185 10200CAACACTAATCTCAGT  4 1697 1246441 N/A N/A 10520 10535 ATAACATGGCTGGCAT 141698 1246467 N/A N/A 11235 11250 CATAGACATGTGTTCA 52 1699 1246493 N/AN/A 11568 11583 TGACAATGGTTGATAG 16 1700 1246519 N/A N/A 11953 11968GTATCATTTGGCTTAA 29 1701 1246545 N/A N/A 12254 12269 TTCTATTAGTTGGCCT 281702 1246571 N/A N/A 12610 12625 TAATTTTCGGGTTCTT 40 1703 1246597 N/AN/A 12723 12738 GGATTAATTCCCTTCC 10 1704 1246623 N/A N/A 13594 13609GATAGAGCACATGGCC 20 1705 1246649 N/A N/A 13842 13857 CACGAAGCCTGAATGC 241706 1246675 N/A N/A 14011 14026 CACAATCTAGCAACCT 40 1707 1246701 N/AN/A 14170 14185 GAATAGCAAGCCAACA 64 1708 1246727 N/A N/A 14391 14406ACATAGGCTTAGTGTA  0 1709 1246753 N/A N/A 14616 14631 CGAATTATTTCTTGCG 581710 1246779 N/A N/A 15280 15295 CTCAAAGCCTGTTGGA 10 1711 1246805 N/AN/A 15380 15395 AAAATGGTGGCGAGGC  0 1712 1246831* N/A N/A 15751 15766GTACTTACTTCTGTAG  0 1713 1246857 N/A N/A 16292 16307 TTAGTTAGAATAGTCT  81714 1246883 N/A N/A 17144 17159 AGTAAATTGAATAGCC 39 1715 1246909 N/AN/A 18000 18015 GCTTATGAAGTTAGTA 67 1716 1246935 N/A N/A 18798 18813CGTAAAATTGTGTCTC 43 1717 1246961 N/A N/A 19397 19412 GCATAAGAGATGAGTA 331718 1246987 N/A N/A 19610 19625 ATCTATTATGCACTCT 24 1719 1247013 N/AN/A 19819 19834 CATAGTTCAAATTGGA 39 1720 1247039 N/A N/A 20138 20153GGGAAAAAGTGTGTTC 20 1721 1247065 N/A N/A 20395 20410 GTAATTGCTATAGTAA 331722 1247091 N/A N/A 20604 20619 ATTTAGAATACGCTGA 19 1723

TABLE 23Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2  HSD17B13 SEQCompound Start Stop Start Stop (% ID Number Site Site Site SiteSequence (5′ to 3′) Inhibition) NO 1245090   26   41  3120  3135TGGTTCAGTCCTTGTG 50 1724 1245116  107  122  3201  3216 CAAGTAGGAGTAGATG 5 1725 1245142  172  187  3266  3281 ATGAGAACAATCTCCC 65 1726 1245168 247  262  3341  3356 CACAGAACCAATATGC 54 1727 1245194  295  310  7584 7599 TTTCGGCACTCAGCTG 29 1728 1245220  355  370  7644  7659CGATAGATCTCTTCTC 15 1729 1245246  398  413  8792  8807 GATTGTTACATCACCC65 1730 1245272  428  443  8822  8837 TGGATATACTGTCCCA 24 1731 1245298 465  480  8859  8874 TGGTAATCTCTTCATC 23 1732 1245324  500  515  8894 8909 CCAAAAATGTCCTAGG 38 1733 1245350  557  572 10443 10458TGTGACGATGTGGCCA 42 1734 1245376  610  625 N/A N/A GAACAATATGGGATGA 261735 1245402  660  675 12078 12093 GAAGTTCTGATGTCAG  0 1736 1245428  751 766 N/A N/A CATAATCTTGTGCTTG 37 1737 1245454  786  801 15667 15682GACTTCTTACGACTTC 38 1738 1245480  838  853 15719 15734 ATATACGATGGAACAA 0 1739 1245506*  903  918 20718 20733 GCATACGATTTAAAAT  0 1740 1245532* 969  984 20784 20799 GCTGGAGCTTATTTAT 16 1741 1245558 1010 1025 2082520840 GATTCGAAACTATTCA 57 1742 1245584 1084 1099 20899 20914CTGCTGCTAGTGCCAA 57 1743 1245610 1256 1271 21071 21086 GCTTTTGTCCACCTTT68 1744 1245636 1308 1323 21123 21138 TAAACCTTCCCTGTGT 17 1745 12456621337 1352 21152 21167 TACAGATTGGAATGCT 46 1746 1245688 1380 1395 2119521210 TGTGCACTCATTCTGT 18 1747 1245714 1419 1434 21234 21249GTTGAGATAAAGCTGC 54 1748 1245740 1495 1510 21310 21325 TTGCACCGTTTTGGGC45 1749 1245766 1553 1568 21368 21383 TTGGTGGACTTCAGAG  8 1750 12457921602 1617 21417 21432 ATGTATCTTATAAGAC  0 1751 1245818 1706 1721 2152121536 CTGGGACCAAGGATAT 32 1752 1245841 1765 1780 21580 21595GTACAGTTCCTTTTCC 50   38 1245844 1768 1783 21583 21598 CCAGTACAGTTCCTTT66 1753 1245870 1802 1817 21617 21632 TCTTCTCTTGGGTCCA 59 1754 12458962199 2214 22014 22029 CAAGATTAGTCTTGAT 27 1755 1245922 N/A N/A  3357 3372 TACCTTATTAATATCC 54 1756 1245948 N/A N/A  3547  3562AAAAATCGCTGCTTAG 25 1757 1245974 N/A N/A  3834  3849 GACTACGGACTGGCAA 601758 1246000 N/A N/A  4414  4429 AGAAAGTTCATTCGAA 61 1759 1246026 N/AN/A  5057  5072 TTACAGCCTTAGAGTG 21 1760 1246052 N/A N/A  5200  5215TTTGAACCGTATTCCC 69 1761 1246065 N/A N/A  5659  5674 ATAAGTTACCAGAGCA 77  48 1246078 N/A N/A  5760  5775 GAATAGGAGAGTCTTT 58 1762 1246104 N/AN/A  5955  5970 ATTGAGATGACAGTGG 70 1763 1246130 N/A N/A  6211  6226CCATAACCATAGGACA 63 1764 1246156 N/A N/A  6455  6470 TGCTAAGTAGTAATTC 321765 1246182 N/A N/A  7121  7136 AAGATTAGTTAACCTT 24 1766 1246208 N/AN/A  7851  7866 CAATAATAATGGGCAG 43 1767 1246234 N/A N/A  8205  8220GAGTCATAATTTGCTT 57 1768 1246260 N/A N/A  8672  8687 CTATTGTATGAGGTCT 421769 1246286 N/A N/A  8978  8993 CCAGAAGTATGTGAAC  8 1770 1246312 N/AN/A  9330  9345 CCTATATACATCCAAG 53 1771 1246338 N/A N/A  9514  9529ACTAATATTGAGGCAC 19 1772 1246364 N/A N/A  9662  9677 AGCTATAGGTAGCTAA  01773 1246390 N/A N/A  9943  9958 CCACACTAATGAATCA 43 1774 1246416 N/AN/A 10202 10217 TATGGTAAGCCCCATG 30 1775 1246442 N/A N/A 10522 10537ATATAACATGGCTGGC 29 1776 1246468 N/A N/A 11236 11251 ACATAGACATGTGTTC 351777 1246494 N/A N/A 11590 11605 CTCAATAACTGAGTTA  4 1778 1246520 N/AN/A 11962 11977 GAGAAGGCGGTATCAT 48 1779 1246546 N/A N/A 12255 12270CTTCTATTAGTTGGCC 11 1780 1246572 N/A N/A 12611 12626 TTAATTTTCGGGTTCT 311781 1246598 N/A N/A 12724 12739 AGGATTAATTCCCTTC 19 1782 1246624 N/AN/A 13595 13610 GGATAGAGCACATGGC 33 1783 1246650 N/A N/A 13845 13860GTACACGAAGCCTGAA 42 1784 1246676 N/A N/A 14012 14027 TCACAATCTAGCAACC  41785 1246702 N/A N/A 14171 14186 TGAATAGCAAGCCAAC  4 1786 1246728 N/AN/A 14393 14408 AAACATAGGCTTAGTG 16 1787 1246754 N/A N/A 14724 14739AATACCCTTGGTGGAG 16 1788 1246780 N/A N/A 15312 15327 TAATCATGGGACAGGA 151789 1246806 N/A N/A 15381 15396 CAAAATGGTGGCGAGG 10 1790 1246832 N/AN/A 15771 15786 GTATTTGGGTGTTCTG 36 1791 1246858 N/A N/A 16293 16308TTTAGTTAGAATAGTC 15 1792 1246884 N/A N/A 17227 17242 GTACAAATTTATGCCA 451793 1246910 N/A N/A 18001 18016 GGCTTATGAAGTTAGT 59 1794 1246936 N/AN/A 18812 18827 TAATTGCATCTGCTCG 46 1795 1246962 N/A N/A 19398 19413TGCATAAGAGATGAGT 19 1796 1246988 N/A N/A 19611 19626 TATCTATTATGCACTC 481797 1247014 N/A N/A 19820 19835 TCATAGTTCAAATTGG 47 1798 1247040 N/AN/A 20172 20187 CAATTATGAATCTGCA 25 1799 1247066 N/A N/A 20396 20411AGTAATTGCTATAGTA 48 1800 1247092 N/A N/A 20605 20620 CATTTAGAATACGCTG 251801

TABLE 24Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2  HSD17B13 SEQCompound Start Stop Start Stop (% ID Number Site Site Site SiteSequence (5′ to 3′) Inhibition) NO 1245091   27   42  3121  3136CTGGTTCAGTCCTTGT 63 1802 1245117  108  123  3202  3217 CCAAGTAGGAGTAGAT19 1803 1245143  175  190  3269  3284 GTAATGAGAACAATCT 48 1804 1245169 248  263  3342  3357 CCACAGAACCAATATG 49 1805 1245195  296  311  7585 7600 TTTTCGGCACTCAGCT 13 1806 1245221  356  371  7645  7660GCGATAGATCTCTTCT 24 1807 1245247  399  414  8793  8808 CGATTGTTACATCACC47 1808 1245273  429  444  8823  8838 CTGGATATACTGTCCC 20 1809 1245299 469  484  8863  8878 GTCTTGGTAATCTCTT 37 1810 1245325  511  526 N/A N/AGCTTTTGTGATCCAAA 43 1811 1245351  558  573 10444 10459 CTGTGACGATGTGGCC28 1812 1245377  611  626 N/A N/A GGAACAATATGGGATG 36 1813 1245403  665 680 12083 12098 GGCCTGAAGTTCTGAT  0 1814 1245429  752  767 N/A N/ACCATAATCTTGTGCTT 32 1815 1245455  787  802 15668 15683 AGACTTCTTACGACTT41 1816 1245481  839  854 15720 15735 GATATACGATGGAACA 46 1817 1245507* 904  919 20719 20734 TGCATACGATTTAAAA 18 1818 1245533*  970  985 2078520800 GGCTGGAGCTTATTTA 57 1819 1245559 1011 1026 20826 20841TGATTCGAAACTATTC 29 1820 1245585 1085 1100 20900 20915 ACTGCTGCTAGTGCCA47 1821 1245611 1257 1272 21072 21087 AGCTTTTGTCCACCTT 57 1822 12456371310 1325 21125 21140 CTTAAACCTTCCCTGT 22 1823 1245663 1338 1353 2115321168 CTACAGATTGGAATGC 52 1824 1245689 1381 1396 21196 21211CTGTGCACTCATTCTG 51 1825 1245715 1420 1435 21235 21250 GGTTGAGATAAAGCTG76 1826 1245741 1496 1511 21311 21326 GTTGCACCGTTTTGGG 56 1827 12457671554 1569 21369 21384 TTTGGTGGACTTCAGA 16 1828 1245793 1613 1628 2142821443 CACCTTTCATAATGTA 59 1829 1245819 1707 1722 21522 21537TCTGGGACCAAGGATA 30 1830 1245841 1765 1780 21580 21595 GTACAGTTCCTTTTCC50   38 1245845 1769 1784 21584 21599 GCCAGTACAGTTCCTT 61 1831 12458712174 2189 21989 22004 GTCGGATTATTTTTTC 61 1832 1245897 2200 2215 2201522030 ACAAGATTAGTCTTGA 45 1833 1245923 N/A N/A  3368  3383GATGTATACATTACCT 67 1834 1245949 N/A N/A  3549  3564 ATAAAAATCGCTGCTT 111835 1245975 N/A N/A  3877  3892 ATCATATGCTAAGTGC 73 1836 1246001 N/AN/A  4415  4430 CAGAAAGTTCATTCGA 67 1837 1246027 N/A N/A  5061  5076TACATTACAGCCTTAG 75 1838 1246053 N/A N/A  5204  5219 GTTTTTTGAACCGTAT 711839 1246065 N/A N/A  5659  5674 ATAAGTTACCAGAGCA 74   48 1246079 N/AN/A  5761  5776 AGAATAGGAGAGTCTT 64 1840 1246105 N/A N/A  5957  5972GTATTGAGATGACAGT 68 1841 1246131 N/A N/A  6212  6227 CCCATAACCATAGGAC 471842 1246157 N/A N/A  6464  6479 GCAGTAAAGTGCTAAG 83 1843 1246183 N/AN/A  7122  7137 GAAGATTAGTTAACCT 13 1844 1246209 N/A N/A  7938  7953CATATTCCCTGATGAT 14 1845 1246235 N/A N/A  8238  8253 AACTACATGACCTGGG 271846 1246261 N/A N/A  8674  8689 TTCTATTGTATGAGGT  0 1847 1246287 N/AN/A  8980  8995 GTCCAGAAGTATGTGA  9 1848 1246313 N/A N/A  9331  9346TCCTATATACATCCAA 45 1849 1246339 N/A N/A  9515  9530 CACTAATATTGAGGCA 311850 1246365 N/A N/A  9663  9678 CAGCTATAGGTAGCTA  0 1851 1246391 N/AN/A  9966  9981 TAGTGTAAGCTGAGAG 75 1852 1246417 N/A N/A 10203 10218GTATGGTAAGCCCCAT 36 1853 1246443 N/A N/A 10523 10538 TATATAACATGGCTGG  81854 1246469 N/A N/A 11238 11253 TGACATAGACATGTGT 42 1855 1246495 N/AN/A 11621 11636 CTGTAGGACTCTGCTC 48 1856 1246521 N/A N/A 11963 11978TGAGAAGGCGGTATCA 20 1857 1246547 N/A N/A 12337 12352 CCCTAATGTGTTTTCC 251858 1246573 N/A N/A 12612 12627 CTTAATTTTCGGGTTC 37 1859 1246599 N/AN/A 12725 12740 TAGGATTAATTCCCTT  0 1860 1246625 N/A N/A 13601 13616AATACAGGATAGAGCA  0 1861 1246651 N/A N/A 13859 13874 TAGGAAAGCTCATGGT 271862 1246677 N/A N/A 14018 14033 GGAAATTCACAATCTA 22 1863 1246703 N/AN/A 14172 14187 TTGAATAGCAAGCCAA 31 1864 1246729 N/A N/A 14394 14409TAAACATAGGCTTAGT 34 1865 1246755 N/A N/A 14726 14741 TAAATACCCTTGGTGG  71866 1246781 N/A N/A 15313 15328 TTAATCATGGGACAGG 27 1867 1246807 N/AN/A 15382 15397 TCAAAATGGTGGCGAG 31 1868 1246833 N/A N/A 15772 15787AGTATTTGGGTGTTCT 17 1869 1246859 N/A N/A 16327 16342 TCACTATATTGCATTC 351870 1246885 N/A N/A 17239 17254 AGGGAATGTTATGTAC 49 1871 1246911 N/AN/A 18012 18027 AAAAGGCCCAAGGCTT 30 1872 1246937 N/A N/A 18813 18828GTAATTGCATCTGCTC 51 1873 1246963 N/A N/A 19399 19414 ATGCATAAGAGATGAG 301874 1246989 N/A N/A 19649 19664 CTATGCAAGCCTTCAC 19 1875 1247015 N/AN/A 19827 19842 GTAATATTCATAGTTC 49 1876 1247041 N/A N/A 20173 20188CCAATTATGAATCTGC 61 1877 1247067 N/A N/A 20397 20412 TAGTAATTGCTATAGT  71878 1247093 N/A N/A 20606 20621 TCATTTAGAATACGCT 20 1879

TABLE 25Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2  HSD17B13 SEQCompound Start Stop Start Stop (% ID Number Site Site Site SiteSequence (5′ to 3′) Inhibition) NO 1245092   31   46  3125  3140CCTTCTGGTTCAGTCC 72 1880 1245118  109  124  3203  3218 TCCAAGTAGGAGTAGA24 1881 1245144  176  191  3270  3285 AGTAATGAGAACAATC 45 1882 1245170 249  264  3343  3358 CCCACAGAACCAATAT 16 1883 1245196  297  312  7586 7601 GTTTTCGGCACTCAGC 51 1884 1245222  357  372  7646  7661AGCGATAGATCTCTTC 31 1885 1245248  400  415  8794  8809 ACGATTGTTACATCAC53 1886 1245274  430  445  8824  8839 GCTGGATATACTGTCC 36 1887 1245300 471  486  8865  8880 ATGTCTTGGTAATCTC 23 1888 1245326  513  528 N/A N/AGTGCTTTTGTGATCCA 62 1889 1245352  559  574 10445 10460 ACTGTGACGATGTGGC40 1890 1245378  612  627 N/A N/A TGGAACAATATGGGAT 46 1891 1245404  667 682 12085 12100 AAGGCCTGAAGTTCTG  5 1892 1245430  755  770 N/A N/AAGGCCATAATCTTGTG 33 1893 1245456  788  803 15669 15684 CAGACTTCTTACGACT33 1894 1245482  840  855 15721 15736 TGATATACGATGGAAC 13 1895 1245508* 905  920 20720 20735 CTGCATACGATTTAAA 32 1896 1245534*  971  986 2078620801 TGGCTGGAGCTTATTT 87 1897 1245560 1012 1027 20827 20842TTGATTCGAAACTATT 55 1898 1245586 1086 1101 20901 20916 GACTGCTGCTAGTGCC67 1899 1245612 1258 1273 21073 21088 TAGCTTTTGTCCACCT 60 1900 12456381312 1327 21127 21142 GTCTTAAACCTTCCCT 63 1901 1245664 1339 1354 2115421169 GCTACAGATTGGAATG 47 1902 1245690 1383 1398 21198 21213AGCTGTGCACTCATTC 57 1903 1245716 1421 1436 21236 21251 AGGTTGAGATAAAGCT74 1904 1245742 1497 1512 21312 21327 AGTTGCACCGTTTTGG 55 1905 12457681556 1571 21371 21386 CTTTTGGTGGACTTCA 10 1906 1245794 1615 1630 2143021445 GTCACCTTTCATAATG 45 1907 1245820 1708 1723 21523 21538CTCTGGGACCAAGGAT 51 1908 1245841 1765 1780 21580 21595 GTACAGTTCCTTTTCC55   38 1245846 1770 1785 21585 21600 AGCCAGTACAGTTCCT 58 1909 12458722175 2190 21990 22005 AGTCGGATTATTTTTT 42 1910 1245898 2201 2216 2201622031 AACAAGATTAGTCTTG 40 1911 1245924 N/A N/A  3401  3416CATATCTTACTCTGTG 47 1912 1245950 N/A N/A  3550  3565 CATAAAAATCGCTGCT 451913 1245976 N/A N/A  3882  3897 CGTTTATCATATGCTA 88 1914 1246002 N/AN/A  4416  4431 CCAGAAAGTTCATTCG 81 1915 1246028 N/A N/A  5062  5077TTACATTACAGCCTTA 67 1916 1246054 N/A N/A  5218  5233 TTAAACTCCAATGTGT 361917 1246065 N/A N/A  5659  5674 ATAAGTTACCAGAGCA 82   48 1246080 N/AN/A  5800  5815 CTCAAATAGCCTTTTG 64 1918 1246106 N/A N/A  5979  5994CCTGAAAAGCCCTATT  0 1919 1246132 N/A N/A  6222  6237 ACCAAACTTGCCCATA 461920 1246158 N/A N/A  6465  6480 GGCAGTAAAGTGCTAA 62 1921 1246184 N/AN/A  7123  7138 TGAAGATTAGTTAACC 21 1922 1246210 N/A N/A  7941  7956ATCCATATTCCCTGAT 26 1923 1246236 N/A N/A  8239  8254 TAACTACATGACCTGG 371924 1246262 N/A N/A  8688  8703 GATGAGAGTCTTTCTT 26 1925 1246288 N/AN/A  9000  9015 AAAGATCTGGCCAGTT  3 1926 1246314 N/A N/A  9332  9347ATCCTATATACATCCA 76 1927 1246340 N/A N/A  9516  9531 ACACTAATATTGAGGC 681928 1246366 N/A N/A  9712  9727 GAACATACATTGTTGC 58 1929 1246392 N/AN/A  9972  9987 GTTGAGTAGTGTAAGC 53 1930 1246418 N/A N/A 10209 10224TTATTGGTATGGTAAG 14 1931 1246444 N/A N/A 10728 10743 GTAATTGGCTCTTGAG 441932 1246470 N/A N/A 11239 11254 ATGACATAGACATGTG 23 1933 1246496 N/AN/A 11652 11667 CTACAAAACTGGTATC  0 1934 1246522 N/A N/A 11982 11997ACCAATCCTCAGCTTT 11 1935 1246548 N/A N/A 12353 12368 GATCATTCCTGCTAGT 351936 1246574 N/A N/A 12613 12628 GCTTAATTTTCGGGTT 36 1937 1246600 N/AN/A 12726 12741 TTAGGATTAATTCCCT 14 1938 1246626 N/A N/A 13603 13618ACAATACAGGATAGAG 23 1939 1246652 N/A N/A 13860 13875 TTAGGAAAGCTCATGG 261940 1246678 N/A N/A 14026 14041 CTTACTAAGGAAATTC 19 1941 1246704 N/AN/A 14174 14189 CCTTGAATAGCAAGCC 61 1942 1246730 N/A N/A 14395 14410ATAAACATAGGCTTAG 41 1943 1246756 N/A N/A 14728 14743 TCTAAATACCCTTGGT 261944 1246782 N/A N/A 15314 15329 ATTAATCATGGGACAG 20 1945 1246808 N/AN/A 15383 15398 ATCAAAATGGTGGCGA 20 1946 1246834 N/A N/A 15773 15788TAGTATTTGGGTGTTC 27 1947 1246860 N/A N/A 16377 16392 ACCAAACTTCCAGCAG 311948 1246886 N/A N/A 17675 17690 CAAAACCTTTGTTGCC 14 1949 1246912 N/AN/A 18015 18030 TCAAAAAGGCCCAAGG 46 1950 1246938 N/A N/A 18814 18829AGTAATTGCATCTGCT 42 1951 1246964 N/A N/A 19404 19419 CAGGAATGCATAAGAG 331952 1246990 N/A N/A 19662 19677 ACCAGAATCCATTCTA 60 1953 1247016 N/AN/A 19860 19875 AATCAATCTGTCTGAA 34 1954 1247042 N/A N/A 20174 20189CCCAATTATGAATCTG 62 1955 1247068 N/A N/A 20398 20413 ATAGTAATTGCTATAG 361956 1247094 N/A N/A 20607 20622 GTCATTTAGAATACGC 46 1957

TABLE 26Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2 HSD17B13 SEQCompound Start Stop Start Stop (% ID Number Site Site Site SiteSequence (5′ to 3′) Inhibition) NO 1245093   58   73  3152  3167ATGTTCATGGCTTTGC 73 1958 1245119  110  125  3204  3219 CTCCAAGTAGGAGTAG 5 1959 1245145  180  195  3274  3289 CTCCAGTAATGAGAAC 40 1960 1245171 250  265  3344  3359 TCCCACAGAACCAATA 24 1961 1245197  298  313  7587 7602 AGTTTTCGGCACTCAG 16 1962 1245223  358  373  7647  7662GAGCGATAGATCTCTT  0 1963 1245249  401  416  8795  8810 CACGATTGTTACATCA37 1964 1245275  431  446  8825  8840 GGCTGGATATACTGTC 18 1965 1245301 472  487  8866  8881 AATGTCTTGGTAATCT 20 1966 1245327  514  529 N/A N/AAGTGCTTTTGTGATCC 25 1967 1245353  560  575 10446 10461 CACTGTGACGATGTGG10 1968 1245379  613  628 N/A N/A CTGGAACAATATGGGA 38 1969 1245405  669 684 12087 12102 CCAAGGCCTGAAGTTC 20 1970 1245431  758  773 N/A N/ATACAGGCCATAATCTT 16 1971 1245457  789  804 15670 15685 TCAGACTTCTTACGAC36 1972 1245483  841  856 15722 15737 TTGATATACGATGGAA 38 1973 1245509* 906  921 20721 20736 TCTGCATACGATTTAA 44 1974 1245535*  972  987 2078720802 CTGGCTGGAGCTTATT 82 1975 1245561 1013 1028 20828 20843ATTGATTCGAAACTAT 22 1976 1245587 1087 1102 20902 20917 TGACTGCTGCTAGTGC50 1977 1245613 1259 1274 21074 21089 GTAGCTTTTGTCCACC 63 1978 12456391313 1328 21128 21143 AGTCTTAAACCTTCCC 77 1979 1245665 1340 1355 2115521170 GGCTACAGATTGGAAT 23 1980 1245691 1384 1399 21199 21214TAGCTGTGCACTCATT 40 1981 1245717 1422 1437 21237 21252 CAGGTTGAGATAAAGC49 1982 1245743 1498 1513 21313 21328 GAGTTGCACCGTTTTG 48 1983 12457691557 1572 21372 21387 ACTTTTGGTGGACTTC  0 1984 1245795 1616 1631 2143121446 GGTCACCTTTCATAAT 57 1985 1245821 1709 1724 21524 21539TCTCTGGGACCAAGGA 56 1986 1245841 1765 1780 21580 21595 GTACAGTTCCTTTTCC44   38 1245847 1771 1786 21586 21601 TAGCCAGTACAGTTCC 52 1987 12458732176 2191 21991 22006 GAGTCGGATTATTTTT 44 1988 1245899 2204 2219 2201922034 CAAAACAAGATTAGTC 18 1989 1245925 N/A N/A  3403  3418TACATATCTTACTCTG 40 1990 1245951 N/A N/A  3551  3566 TCATAAAAATCGCTGC 261991 1245977 N/A N/A  3902  3917 GTTTATCATGTGCCAC 83 1992 1246003 N/AN/A  4434  4449 GTAAATTCTTGCTATC 40 1993 1246029 N/A N/A  5063  5078GTTACATTACAGCCTT 71 1994 1246055 N/A N/A  5221  5236 AGCTTAAACTCCAATG 401995 1246065 N/A N/A  5659  5674 ATAAGTTACCAGAGCA 80   48 1246081 N/AN/A  5816  5831 TCAAAGTCAGTATCCC 79 1996 1246107 N/A N/A  5983  5998GATACCTGAAAAGCCC 49 1997 1246133 N/A N/A  6223  6238 TACCAAACTTGCCCAT 331998 1246159 N/A N/A  6473  6488 ATGTAATAGGCAGTAA 33 1999 1246185 N/AN/A  7481  7496 ACAATTAACATTCGGC 77 2000 1246211 N/A N/A  7950  7965TAGGAAGTGATCCATA 30 2001 1246237 N/A N/A  8240  8255 ATAACTACATGACCTG 292002 1246263 N/A N/A  8693  8708 CCAAAGATGAGAGTCT 19 2003 1246289 N/AN/A  9001  9016 CAAAGATCTGGCCAGT  1 2004 1246315 N/A N/A  9346  9361CAAAAGTGTCCTCGAT  5 2005 1246341 N/A N/A  9517  9532 TACACTAATATTGAGG 302006 1246367 N/A N/A  9713  9728 TGAACATACATTGTTG 29 2007 1246393 N/AN/A  9976  9991 GACAGTTGAGTAGTGT 46 2008 1246419 N/A N/A 10210 10225TTTATTGGTATGGTAA 25 2009 1246445 N/A N/A 10729 10744 TGTAATTGGCTCTTGA  02010 1246471 N/A N/A 11248 11263 ACCAAGGCCATGACAT 17 2011 1246497 N/AN/A 11653 11668 TCTACAAAACTGGTAT  9 2012 1246523 N/A N/A 11983 11998AACCAATCCTCAGCTT  0 2013 1246549 N/A N/A 12411 12426 GATCAAATGTATGTGC 252014 1246575 N/A N/A 12614 12629 GGCTTAATTTTCGGGT 17 2015 1246601 N/AN/A 12727 12742 TTTAGGATTAATTCCC 16 2016 1246627 N/A N/A 13604 13619GACAATACAGGATAGA 43 2017 1246653 N/A N/A 13861 13876 CTTAGGAAAGCTCATG  02018 1246679 N/A N/A 14027 14042 CCTTACTAAGGAAATT 28 2019 1246705 N/AN/A 14194 14209 TGTGATTGAGTTCTCC 62 2020 1246731 N/A N/A 14397 14412TCATAAACATAGGCTT 58 2021 1246757 N/A N/A 14729 14744 CTCTAAATACCCTTGG  72022 1246783 N/A N/A 15315 15330 GATTAATCATGGGACA  9 2023 1246809 N/AN/A 15384 15399 TATCAAAATGGTGGCG 18 2024 1246835 N/A N/A 15774 15789TTAGTATTTGGGTGTT 29 2025 1246861 N/A N/A 16382 16397 TCCCAACCAAACTTCC 822026 1246887 N/A N/A 17766 17781 GCATATTCATTTGGCC  6 2027 1246913 N/AN/A 18018 18033 GTTTCAAAAAGGCCCA 39 2028 1246939 N/A N/A 18815 18830TAGTAATTGCATCTGC 51 2029 1246965 N/A N/A 19436 19451 TGGAGGAAAGCTTCAA 102030 1246991 N/A N/A 19675 19690 ACCAAGAGACACCACC 41 2031 1247017 N/AN/A 19889 19904 CTTACGACAGGTCATC 39 2032 1247043 N/A N/A 20185 20200TTAGAAGTCAGCCCAA 37 2033 1247069 N/A N/A 20400 20415 CTATAGTAATTGCTAT  02034 1247095 N/A N/A 20608 20623 GGTCATTTAGAATACG 39 2035

Example 2: Dose-Dependent Inhibition of Human HSD17B13 in HepaRG Cellsby cEt Gapmers

Certain modified oligonucleotides described in the studies aboveexhibiting significant in vitro inhibition of HSD17B13 RNA were selectedand tested at various doses in HepaRG cells.

The modified oligonucleotides were tested in a series of experimentsusing the same culture conditions. The results for each experiment arepresented in separate tables shown below. Cultured HepaRG cells at adensity of 30,000 cells per well were transfected using electroporationwith modified oligonucleotides diluted to different concentrations asspecified in the Tables below. After a treatment period of approximately24 hours, HSD17B13 RNA levels were measured as previously describedusing the Human HSD17B13 primer-probe set RTS43553. HSD17B13 RNA levelswere normalized to total RNA, as measured by RIBOGREEN®. Results arepresented in the tables below as percent inhibition of HSD17B13,relative to untreated control cells.

The half maximal inhibitory concentration (IC₅₀) of each modifiedoligonucleotide was calculated using a linear regression on a log/linearplot of the data in excel and is also presented in the Tables below.

TABLE 27 Multi-dose assay of modified oligonucleotides in HepaRG cellsION % Inhibition IC50 No. 6 nM 32 nM 160 nM 800 nM 4000 nM (μM) 12456510 6 24 57 82 0.6 1245927 0 19 55 80 90 0.2 1245930 0 0 30 77 86 0.41245957 8 8 49 77 87 0.2 1245984 12 14 62 78 90 0.1 1246065 0 10 46 6589 0.3 1246066 0 13 35 58 76 0.5 1246068 0 5 30 61 83 0.5 1246110 3 1244 82 87 0.2 1246115 8 14 45 75 89 0.2 1246116 6 17 48 72 83 0.2 12461343 21 55 79 91 0.2 1246163 2 15 43 75 92 0.2

TABLE 28 Multi-dose assay of modified oligonucleotides in HepaRG cellsION % Inhibition IC50 No. 6 nM 32 nM 160 nM 800 nM 4000 nM (μM) 12456810 12 38 72 90 0.3 1245790 1 8 37 67 93 0.3 1245968 15 23 49 75 93 0.21245976 0 16 49 73 88 0.2 1245977 0 10 41 75 77 0.3 1245999 1 14 48 8290 0.2 1246022 13 24 56 83 93 0.1 1246023 13 24 66 90 93 0.1 1246104 0 035 67 87 0.4 1246157 0 22 40 75 84 0.3 1246226 11 7 40 71 88 0.3 124666789 95 97 98 100 <0.006 1246853 0 2 11 57 82 0.7 1246861 4 0 12 31 67 2.6

Example 3: Antisense Inhibition of Human HSD17B13 in HepaRG Cells by cEtGapmers

Additional modified oligonucleotides complementary to an HSD17B13nucleic acid were synthesized and tested for their effect on HSD17B13RNA levels in vitro. The modified oligonucleotides were tested in aseries of experiments using the same culture conditions. The results foreach experiment are presented in separate tables shown below.

Cultured HepaRG cells at a density of 30,000 cells per well weretransfected using electroporation with 1,000 nM of modifiedoligonucleotide. After a treatment period of approximately 24 hours, RNAwas isolated from the cells and HSD17B13 RNA levels were measured byquantitative real-time RTPCR. Human primer probe set RTS43553 was usedto measure RNA levels. HSD17B13 RNA levels were adjusted according tototal RNA content, as measured by RIBOGREEN®. Results are presented aspercent inhibition of HSD17B13 relative to untreated control cells. Asused herein, a value of ‘0’ indicates that treatment with the modifiedoligonucleotide did not inhibit HSD17B13 mRNA levels. An asterisk (*)indicates that the modified oligonucleotide is complementary to thetarget transcript within the amplicon region of the primer probe set andso, the associated data is not reliable. In such instances, additionalusing alternate primer probe sets must be performed to accurately assessthe potency and efficacy of such modified oligonucleotides.

The modified oligonucleotides described in the tables below were 3-10-3cEt gapmers. The internucleoside linkages throughout each modifiedoligonucleotide were phosphorothioate (P═S) linkages. All cytosineresidues throughout each modified oligonucleotide were5-methylcytosines.

“Start site” indicates the 5′-most nucleoside of the target sequence towhich the modified oligonucleotide is complementary. “Stop site”indicates the 3′-most nucleoside of the target sequence to which themodified oligonucleotide is complementary. As shown in the Tables below,the modified oligonucleotide are complementary to either the humanHSD17B13 mRNA, designated herein as SEQ ID NO: 1 (GENBANK Accession No.NM_178135.4) or to the human HSD17B13 genomic sequence, designatedherein as SEQ ID NO: 2 (the complement of GENBANK Accession No.NC_000004.12 truncated from nucleotides 87301001 to 87326000) or toboth. ‘N/A’ indicates that the modified oligonucleotide is notcomplementary to that particular target sequence with 100%complementarity.

TABLE 29Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2 SEQ Compound StartStop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′)Inhibition NO 1245927 N/A N/A  3433  3448 AGTAGATGGTAAGTCA 91  1211246023 N/A N/A  5046  5061 GAGTGAATCATTCAGT 89 1526 1340071 N/A N/A20191 20206 CAGTTATTAGAAGTCA 85 2036 1340085 N/A N/A 20588 20603GAGTTATCTGGTTTGC 84 2037 1340086 N/A N/A  9335  9350 TCGATCCTATATACAT 402038 1340096 N/A N/A 19711 19726 GCTGAAACTGCTGATT 38 2039 1340099 17631778 21578 21593 ACAGTTCCTTTTCCTG 58 2040 1340104 N/A N/A 10500 10515TACTTACCAATATGGG 13 2041 1340120 N/A N/A 11585 11600 TAACTGAGTTATTCTC 412042 1340158 N/A N/A  6440  6455 CTAAACTAGTGGTAAT 23 2043 1340170 N/AN/A  9657  9672 TAGGTAGCTAATGTAT 34 2044 1340194 N/A N/A 11077 11092TAATTACAACCTGGTT 52 2045 1340201 N/A N/A 14279 14294 GTAAAGGCTGGGTGAG 412046 1340204 N/A N/A 12202 12217 TCATACCACATACCCA 41 2047 1340209 N/AN/A 18520 18535 CTTAGTACCAAGACAC 60 2048 1340231 N/A N/A 16134 16149GATGCTCCATAATAAT 42 2049 1340239 N/A N/A 19912 19927 TGCATCTTAAGATACC 812050 1340247 N/A N/A 16286 16301 AGAATAGTCTTCAGCA 80 2051 1340256 N/AN/A 19532 19547 GGCTAAAATGGTCATC 75 2052 1340276 N/A N/A 19394 19409TAAGAGATGAGTAGGC 46 2053 1340278 N/A N/A 15250 15265 TCTATAGCTAAGTATA  02054 1340279 N/A N/A 17802 17817 TATTCTTATGTCATCC 75 2055 1340290  809 824 15690 15705 ATTGGTAAGTATTCCA 50 2056 1340305 1177 1192 20992 21007TTTAAGAGGCATGAAA 40 2057 1340308 N/A N/A 20111 20126 TCAAGACATTCTAGCC 792058 1340330 N/A N/A 12476 12491 CTAGATACTCAATTTA 30 2059 1340360 N/AN/A 12800 12815 GGCTGTAAGAGTCAGT 88 2060 1340368 N/A N/A 13827 13842CCTACCAAGAGGGTTT 34 2061 1340380 N/A N/A 12005 12020 ATTGTTAGCTAAGGGA 222062 1340390 N/A N/A 14175 14190 GCCTTGAATAGCAAGC 32 2063 1340405 N/AN/A 13598 13613 ACAGGATAGAGCACAT 44 2064 1340412 N/A N/A 14914 14929ACATTAGCAAGCTAAG 52 2065 1340423 N/A N/A  9538  9553 ATCCAGATCTGCCCTA 392066 1340427 N/A N/A  8535  8550 TTGCAAGTTTATCAGT 66 2067 1340432 N/AN/A  4225  4240 GTTTCAACTAAACATG 65 2068 1340438 N/A N/A  3479  3494GGACCAGGGAATTTAT 55 2069 1340439 1255 1270 21070 21085 CTTTTGTCCACCTTTA76 2070 1340448 N/A N/A  5672  5687 GTCAGTAGAGAGCATA 85 2071 1340453 N/AN/A  6084  6099 TTTCACCTCAGGTGAC 52 2072 1340459 N/A N/A  5083  5098CTCGCCTAAAGGAGAT 56 2073 1340465 N/A N/A  5895  5910 TCCTTTGTATTTCGCT 682074 1340479 N/A N/A  6785  6800 CCTCCTTATTTGTTAG 41 2075 1340491 N/AN/A  3699  3714 TTTCAGATCCCGTTCT 45 2076 1340525 N/A N/A  9965  9980AGTGTAAGCTGAGAGT 71 2077 1340542 N/A N/A  5186  5201 CCAACGCAACAGTTTA 772078 1340546 N/A N/A  5647  5662 AGCATTCATCAGATGT 83 2079 1340556 N/AN/A  5268  5283 TTGCAAAATGTGATGC 75 2080 1340563 N/A N/A  3990  4005GTGTTTACAAGTAAGA 79 2081 1340567 N/A N/A  6260  6275 AGATGGGCAAGGCCAC 592082 1340576 N/A N/A 11499 11514 CTGGAGAAGAGTTTAC 38 2083 1340580 N/AN/A  8641  8656 AGACAGACTGTTGAGC 74 2084 1340597 N/A N/A 18036 18051CATAGTTTATATGGAT 56 2085 1340601 N/A N/A 18138 18153 TGTTATCTCAAGTCAG 812086 1340613 N/A N/A  5832  5847 ATGTTAGGACCCAGTC 60 2087 1340661 N/AN/A  9201  9216 TACACTGACAACCCTT 56 2088 1340665 N/A N/A 14601 14616GAGAAATCTAAGAACC 42 2089 1340667 N/A N/A  9936  9951 AATGAATCATGATTGA 332090 1340669 N/A N/A 10000 10015 TGAAATCTTGTGTAAC 43 2091 1340684 N/AN/A  8125  8140 AGTGCTTAGTTCATTG 84 2092 1340685 N/A N/A 16385 16400CAATCCCAACCAAACT 49 2093 1340689 N/A N/A  3600  3615 CTTGGAAGGAGACTGG 602094 1340697 N/A N/A  4661  4676 CCGCCCTTAAGTCATT 53 2095 1340704 N/AN/A  6329  6344 ACTTTCATAGGGAGAC 80 2096 1340705   74   89  3168  3183AAGGATTTCTAGGATG 71 2097 1340722 N/A N/A  5737  5752 TTAGTTGGTAGCTTGC 722098 1340767 N/A N/A  9441  9456 TCCCACAAAACTAACC 24 2099 1340773 N/AN/A  9773  9788 TAGAACTCCCAACCCA 44 2100 1340776 N/A N/A  6732  6747TTACCCCTGGCTTTTC 26 2101 1340785 N/A N/A  7781  7796 ACTACTTCAGTTAGCA 792102 1340792 N/A N/A  9115  9130 GACAGACCAAGTAGCT 39 2103 1340812 N/AN/A 10264 10279 CTTCCAAGCATTCCAT 57 2104 1340813 N/A N/A  7526  7541CCGAAAAAAGTGGAGG 31 2105 1340836 N/A N/A 18694 18709 AAGACTTTGAGACTCT 622106 1340850 N/A N/A  8744  8759 CACTTTCACTGGGTGT  7 2107 1340852 14241439 21239 21254 TCCAGGTTGAGATAAA 70 2108 1340872 1614 1629 21429 21444TCACCTTTCATAATGT 63 2109 1340878 N/A N/A 12627 12642 TTGTTAAGCAGATGGC 842110 1340889 N/A N/A  6597  6612 CTACTTTCAAACCTTG 57 2111 1340903 N/AN/A 20390 20405 TGCTATAGTAATCACA 65 2112

TABLE 30Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2 SEQ Compound StartStop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′)Inhibition NO 1245927 N/A N/A  3433  3448 AGTAGATGGTAAGTCA 84  1211246023 N/A N/A  5046  5061 GAGTGAATCATTCAGT 89 1526 1340078 N/A N/A16295 16310 CCTTTAGTTAGAATAG 37 2113 1340094 N/A N/A 19547 19562ATTGTTTAGCTGATAG 61 2114 1340113 N/A N/A 12667 12682 TGTTAACCTGCAGCAG 392115 1340122 N/A N/A 14192 14207 TGATTGAGTTCTCCAC 48 2116 1340126 N/AN/A 19779 19794 ACATACCACTCTTCTC 35 2117 1340130 N/A N/A 17954 17969TTAGAAACTGCTCCTC 48 2118 1340146 N/A N/A  8132  8147 TTGTTAGAGTGCTTAG 762119 1340149 N/A N/A 11545 11560 CTTGACAATGGTTGCC 58 2120 1340152 N/AN/A 10138 10153 ATAGATCCTTTTTTGG  6 2121 1340154 N/A N/A  6284 6299ACATTCTTCAGGTGTT 88 2122 1340156 N/A N/A 20194 20209 TTGCAGTTATTAGAAG 132123 1340179 N/A N/A 14315 14330 TAAGATGTCCAGGCAT 17 2124 1340197 N/AN/A 10554 10569 GAAGTGTAATGCTCCC 71 2125 1340220 N/A N/A 14611 14626TATTTCTTGCGAGAAA 30 2126 1340241 N/A N/A 16220 16235 TTTATAGACTGGGTAG 592127 1340255 1783 1798 21598 21613 TTTCTTATGTAATAGC 76 2128 1340260 17141729 21529 21544 AAACATCTCTGGGACC 76 2129 1340277 N/A N/A 19914 19929AGTGCATCTTAAGATA 57 2130 1340291 N/A N/A 18540 18555 GAAACTCACTTCCTAC 562131 1340297 N/A N/A 14917 14932 AATACATTAGCAAGCT 45 2132 1340304 697712 12115 12130 AGACATGAGGTTTTGA 59 2133 1340310 N/A N/A 13638 13653GACAATGTGCAGCTCT 67 2134 1340321 N/A N/A  6606  6621 TAAAGCAGGCTACTTT  92135 1340323 N/A N/A 19396 19411 CATAAGAGATGAGTAG 44 2136 1340342 N/AN/A  5279  5294 GAGCTAGACAATTGCA 73 2137 1340350 N/A N/A  9716  9731TAGTGAACATACATTG 23 2138 1340361 N/A N/A  5935  5950 GCTGCTATTTAGGGCA 532139 1340364 N/A N/A  5678  5693 TTCTAGGTCAGTAGAG 58 2140 1340369 14331448 21248 21263 TAAAATATGTCCAGGT 75 2141 1340385 N/A N/A  4389  4404AGACCAAAAAGATGGC 80 2142 1340395 N/A N/A 11794 11809 AACTCTATTGATTGGC 722143 1340416 N/A N/A 12496 12511 AATTCACCTTGACTAA  9 2144 1340419 N/AN/A 12410 12425 ATCAAATGTATGTGCT 73 2145 1340443 N/A N/A 11117 11132CTACAGAGGAGTTTGC 27 2146 1340445 N/A N/A  5847  5862 ACTCCCCAAACATGGA 482147 1340458 N/A N/A  7834  7849 GCTGAGTGGATTACAT 44 2148 1340469 N/AN/A  6456  6471 GTGCTAAGTAGTAATT 58 2149 1340476 815 830 15696 15711TTTCTTATTGGTAAGT 44 2150 1340512 N/A N/A  6736  6751 GAGATTACCCCTGGCT 722151 1340522 N/A N/A  6915  6930 ACTCGGGAAGTTTAGA 26 2152 1340533 N/AN/A  9456  9471 GTTGATATTTCCATCT 55 2153 1340543 N/A N/A 20115 20130AGCATCAAGACATTCT 79 2154 1340549 N/A N/A  9968  9983 AGTAGTGTAAGCTGAG 882155 1340552 N/A N/A 12802 12817 CAGGCTGTAAGAGTCA 56 2156 1340555 N/AN/A  5158 5173 GCCAAACTGCTACTGT 73 2157 1340558 N/A N/A 15423 15438ATATCCAGTAGGTGTG 55 2158 1340606 N/A N/A 18046 18061 CAAGTTTGTTCATAGT 782159 1340614 1311 1326 21126 21141 TCTTAAACCTTCCCTG 21 2160 1340651 N/AN/A  9344  9359 AAAGTGTCCTCGATCC 36 2161 1340671 N/A N/A 10293 10308TGAGAGAACTTATACA 32 2162 1340673 N/A N/A  5191  5206 TATTCCCAACGCAACA 622163 1340674 N/A N/A  4663  4678 ACCCGCCCTTAAGTCA 48 2164 1340679 N/AN/A  5758  5773 ATAGGAGAGTCTTTCA 77 2165 1340681 N/A N/A  8547  8562GCACATCATGTTTTGC 44 2166 1340683 N/A N/A  9947  9962 TACACCACACTAATGA 262167 1340696 N/A N/A  8656  8671 CTCAGAGTTCAGGCAA 67 2168 1340713 N/AN/A  6191  6206 GACAGAGCAATTTACT 55 2169 1340734 N/A N/A  8964  8979ACTCCGTTATAAGTTT 42 2170 1340747 218 233  3312  3327 AAATTCATAAGTAGTC 392171 1340757 N/A N/A 18143 18158 CCTTATGTTATCTCAA 67 2172 1340761 N/AN/A  4068  4083 CCTTACCAGAATTTAC 63 2173 1340762 N/A N/A  5651  5666CCAGAGCATTCATCAG 83 2174 1340768 N/A N/A  9210  9225 GAAAAGATGTACACTG 562175 1340770 N/A N/A  3505  3520 CTAACCTGACACATAT 18 2176 1340771 11791194 20994 21009 TTTTTAAGAGGCATGA 60 2177 1340775 N/A N/A  9593  9608AAGAGCTGGTAAAGGT 47 2178 1340798 N/A N/A  3619  3634 GACTTGCCTCATTTAG 692179 1340802 N/A N/A  9793  9808 CCTATGCAAATTCATA 34 2180 1340803 N/AN/A  6333  6348 AAGGACTTTCATAGGG 71 2181 1340824 N/A N/A 20421 20436CAGTAAAATTATGCCT 38 2182 1340831 N/A N/A  3702  3717 AATTTTCAGATCCCGT 742183 1340833 N/A N/A  9117  9132 AAGACAGACCAAGTAG 16 2184 1340837 N/AN/A 13955 13970 ACCTCTAAGTTAGCCC 28 2185 1340845 N/A N/A 18697 18712CAAAAGACTTTGAGAC 22 2186 1340863 N/A N/A 20598 20613 AATACGCTGAGAGTTA 482187 1340874 N/A N/A  7528  7543 TTCCGAAAAAAGTGGA 13 2188 1340891 N/AN/A 16895 16910 CGTCAAATAGGGCTGG 53 2189

TABLE 31Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2 SEQ Compound StartStop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′)Inhibition NO 1245927 N/A N/A  3433  3448 AGTAGATGGTAAGTCA 91  1211246023 N/A N/A  5046  5061 GAGTGAATCATTCAGT 83 1526 1340082 N/A N/A16329 16344 CTTCACTATATTGCAT 50 2190 1340083 N/A N/A 20116 20131CAGCATCAAGACATTC 72 2191 1340092 N/A N/A 16221 16236 TTTTATAGACTGGGTA 532192 1340098 N/A N/A 19818 19833 ATAGTTCAAATTGGAT 48 2193 1340125 N/AN/A 15778 15793 TGTTTTAGTATTTGGG 48 2194 1340131 N/A N/A 18720 18735CACCATGACAGCTTCA 65 2195 1340141 N/A N/A 11213 11228 CTTCTGTAGGTTTTGC 602196 1340142 N/A N/A 17984 17999 TAGTTATCTTCTCACT 52 2197 1340148 22402255 22055 22070 ATGCAAAAGCATTCTA 50 2198 1340164 N/A N/A 11546 11561TCTTGACAATGGTTGC 77 2199 1340183 N/A N/A 11795 11810 TAACTCTATTGATTGG 512200 1340187 N/A N/A 20628 20643 GACAACAGAGTTCTGT  9 2201 1340192 N/AN/A 12498 12513 GAAATTCACCTTGACT 41 2202 1340206 1330 1345 21145 21160TGGAATGCTACTTGAA 85 2203 1340208 N/A N/A  9969  9984 GAGTAGTGTAAGCTGA 802204 1340215 N/A N/A 12416 12431 ACGGTGATCAAATGTA 53 2205 1340221 N/AN/A 16900 16915 AAAACCGTCAAATAGG 28 2206 1340230 N/A N/A 18658 18673TATTCTCCAACTCAGG 54 2207 1340235 N/A N/A 18145 18160 CTCCTTATGTTATCTC 572208 1340245 N/A N/A 15446 15461 TGTTATCAGAAACTTA 44 2209 1340270 N/AN/A  7550  7565 GCTGTAATTAGGAAGA 24 2210 1340274 N/A N/A 10584 10599AGAACCAGGACTCTCC 67 2211 1340275  219  234  3313  3328 CAAATTCATAAGTAGT76 2212 1340284 1467 1482 21282 21297 AAGAGGCTAGGGAAAT 66 2213 1340292N/A N/A 19417 19432 GACAACTGATGTCCAG 12 2214 1340312 N/A N/A 20423 20438GACAGTAAAATTATGC 57 2215 1340314 N/A N/A 18075 18090 TTGTACCCTGTTCTCA 642216 1340320 N/A N/A 14318 14333 AATTAAGATGTCCAGG 13 2217 1340324 N/AN/A  9950  9965 TTCTACACCACACTAA 12 2218 1340329 1181 1196 20996 21011AGTTTTTAAGAGGCAT 75 2219 1340337 N/A N/A 13659 13674 TCACAAAGTCCCTGAC 112220 1340353 N/A N/A  7125  7140 CATGAAGATTAGTTAA 11 2221 1340355 N/AN/A  8657  8672 TCTCAGAGTTCAGGCA 54 2222 1340356 N/A N/A  5680  5695GTTTCTAGGTCAGTAG 73 2223 1340366 N/A N/A  6457  6472 AGTGCTAAGTAGTAAT 712224 1340367 N/A N/A  5870  5885 TAAACCCTGGAGCAGC 66 2225 1340370 N/AN/A  5159  5174 AGCCAAACTGCTACTG 78 2226 1340426 N/A N/A  9597  9612TGTGAAGAGCTGGTAA 41 2227 1340472 N/A N/A  6335  6350 AGAAGGACTTTCATAG 462228 1340475 N/A N/A  8136  8151 AAGTTTGTTAGAGTGC 74 2229 1340484 N/AN/A 12709 12724 CCAGTAAAAAATTGGT 23 2230 1340503 N/A N/A 14613 14628ATTATTTCTTGCGAGA 60 2231 1340514 N/A N/A  9345  9360 AAAAGTGTCCTCGATC 172232 1340515 N/A N/A  5762  5777 AAGAATAGGAGAGTCT 70 2233 1340539 N/AN/A  3721  3736 GACTTTTGTTTGTAGC 74 2234 1340560 N/A N/A  6285  6300TACATTCTTCAGGTGT 61 2235 1340577 N/A N/A  5280  5295 TGAGCTAGACAATTGC 782236 1340603  699  714 12117 12132 AGAGACATGAGGTTTT 77 2237 1340604 N/AN/A 20195 20210 ATTGCAGTTATTAGAA 42 2238 1340617 N/A N/A  3516  3531CCTTCATCTAACTAAC 30 2239 1340636 N/A N/A 12804 12819 CTCAGGCTGTAAGAGT 212240 1340647 N/A N/A  5195  5210 ACCGTATTCCCAACGC 90 2241 1340659 N/AN/A  8965  8980 AACTCCGTTATAAGTT 11 2242 1340664 N/A N/A  3676  3691CCCCTAAGTTATTATC 33 2243 1340690 N/A N/A  9726  9741 TGTGAGAGGATAGTGA 502244 1340724 N/A N/A  4862  4877 AACTGAAACGATCCTC 52 2245 1340725 N/AN/A  9466  9481 GGCAGTTGAAGTTGAT 46 2246 1340727 N/A N/A  8589  8604GTGGGATAAACTGTTC 52 2247 1340746 N/A N/A 19564 19579 TAGCTATTGTCTTTGA 632248 1340781 N/A N/A 13956 13971 TACCTCTAAGTTAGCC 28 2249 1340789 N/AN/A 14193 14208 GTGATTGAGTTCTCCA 80 2250 1340790 N/A N/A  9118  9133CAAGACAGACCAAGTA 27 2251 1340830 N/A N/A  7835  7850 AGCTGAGTGGATTACA 292252 1340834 N/A N/A  6203  6218 ATAGGACATGGAGACA 82 2253 1340835 N/AN/A  5653  5668 TACCAGAGCATTCATC 55 2254 1340838 N/A N/A 10294 10309TTGAGAGAACTTATAC 21 2255 1340839 N/A N/A 19915 19930 GAGTGCATCTTAAGAT 432256 1340841 N/A N/A  4069  4084 GCCTTACCAGAATTTA 75 2257 1340864 N/AN/A  9796  9811 AATCCTATGCAAATTC 42 2258 1340865 1716 1731 21531 21546CTAAACATCTCTGGGA 62 2259 1340870 N/A N/A  4402  4417 CGAATTTCTTCAAAGA 552260 1340875 N/A N/A  5974  5989 AAAGCCCTATTCTTCG 65 2261 1340876 N/AN/A  6626  6641 TGTACAGTAGGCAGTT 75 2262 1340883 N/A N/A  9224  9239CAAGTGACAGCATTGA 48 2263 1340884 N/A N/A  6738  6753 ATGAGATTACCCCTGG 622264 1340885 N/A N/A 10184 10199 AACACTAATCTCAGTA 15 2265 1340892 N/AN/A 14918 14933 TAATACATTAGCAAGC 33 2266

TABLE 32Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2 SEQ Compound StartStop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′)Inhibition NO 1245927 N/A N/A  3433  3448 AGTAGATGGTAAGTCA 59  1211246023 N/A N/A  5046  5061 GAGTGAATCATTCAGT 78 1526 1340075 N/A N/A13957 13972 CTACCTCTAAGTTAGC  6 2267 1340077 1468 1483 21283 21298GAAGAGGCTAGGGAAA 44 2268 1340093 N/A N/A 18744 18759 TATACCTGTTGCCTAG 112269 1340108 N/A N/A 10848 10863 CATATGGTGTACACTG 15 2270 1340129 N/AN/A 16904 16919 GTCAAAAACCGTCAAA 39 2271 1340144  254  269  3348  3363AATATCCCACAGAACC 60 2272 1340151 N/A N/A 11796 11811 ATAACTCTATTGATTG 392273 1340157 N/A N/A  9147  9162 TGCCAAGCTTTGTGTC 38 2274 1340163 N/AN/A 14617 14632 CCGAATTATTTCTTGC 60 2275 1340166 N/A N/A  4412  4427AAAGTTCATTCGAATT 63 2276 1340168 N/A N/A 18086 18101 ACCAATGCAGTTTGTA 752277 1340169 N/A N/A  6460  6475 TAAAGTGCTAAGTAGT 50 2278 1340171 N/AN/A 11553 11568 GTTTTTCTCTTGACAA 59 2279 1340176 N/A N/A 16117 16132GCTCTATTGGGCCAGG 47 2280 1340181 N/A N/A 18176 18191 CGCGAGATGATGTTGC 532281 1340211 N/A N/A 18661 18676 TACTATTCTCCAACTC 47 2282 1340226 11821197 20997 21012 AAGTTTTTAAGAGGCA 77 2283 1340233 N/A N/A 12499 12514AGAAATTCACCTTGAC 39 2284 1340268 N/A N/A 16224 16239 TCTTTTTATAGACTGG 822285 1340273 N/A N/A 11237 11252 GACATAGACATGTGTT 26 2286 1340283 17171732 21532 21547 TCTAAACATCTCTGGG 40 2287 1340286 N/A N/A 19846 19861AACCTATGTGTGCACC 73 2288 1340327 N/A N/A 12418 12433 TAACGGTGATCAAATG 172289 1340332 N/A N/A 10295 10310 TTTGAGAGAACTTATA  0 2290 1340334 N/AN/A  8973  8988 AGTATGTGAACTCCGT 81 2291 1340335 N/A N/A  5654  5669TTACCAGAGCATTCAT 50 2292 1340352 N/A N/A  9970  9985 TGAGTAGTGTAAGCTG 622293 1340375 N/A N/A 19444 19459 TGGGATAGTGGAGGAA 13 2294 1340377 N/AN/A 17986 18001 TATAGTTATCTTCTCA 46 2295 1340386 N/A N/A 14919 14934ATAATACATTAGCAAG  7 2296 1340387 N/A N/A  5873  5888 GGCTAAACCCTGGAGC 362297 1340388 N/A N/A  8164  8179 TATTGTAGGGATTGAA 40 2298 1340397 N/AN/A  3741  3756 CTGTTGCAAGTTCTTC 85 2299 1340398 N/A N/A 13688 13703TTTACTCACTTCTGGT 30 2300 1340415 N/A N/A 12815 12830 CACATAGCTAACTCAG 422301 1340430 N/A N/A  5197  5212 GAACCGTATTCCCAAC 72 2302 1340433 N/AN/A  9467  9482 AGGCAGTTGAAGTTGA 47 2303 1340446 N/A N/A 15491 15506TTAATGCCACCCTACC 19 2304 1340450 N/A N/A  5712  5727 GATTGCACAAACCACA 732305 1340451 N/A N/A  6301  6316 CTAGGAGATATAACAT 40 2306 1340452 N/AN/A  5978  5993 CTGAAAAGCCCTATTC 11 2307 1340454 N/A N/A  7680  7695AATTTGTGAACCTGCA 20 2308 1340468 N/A N/A 20197 20212 ACATTGCAGTTATTAG 422309 1340471 N/A N/A 14385 14400 GCTTAGTGTAGAATTG 16 2310 1340478 N/AN/A  6740  6755 CAATGAGATTACCCCT 16 2311 1340489 N/A N/A  6388  6403GATGATTCTGACTCAT 55 2312 1340498 N/A N/A 20470 20485 TCATTAGGAAAAGTGT 162313 1340521 N/A N/A  8593  8608 AAAGGTGGGATAAACT 33 2314 1340534 N/AN/A 10187 10202 GCCAACACTAATCTCA 40 2315 1340545 N/A N/A 20117 20132ACAGCATCAAGACATT 53 2316 1340547 N/A N/A  4864  4879 TGAACTGAAACGATCC 582317 1340554 N/A N/A  9225  9240 ACAAGTGACAGCATTG 44 2318 1340566  700 715 12118 12133 CAGAGACATGAGGTTT 61 2319 1340574 N/A N/A  9599  9614TATGTGAAGAGCTGGT 63 2320 1340578 N/A N/A  3678  3693 ATCCCCTAAGTTATTA 132321 1340585 N/A N/A  5782  5797 GGATTGCAGAAGAGTA 76 2322 1340610 N/AN/A 20629 20644 TGACAACAGAGTTCTG 11 2323 1340628 N/A N/A 19585 19600TAAACTAAAGTACTTG  1 2324 1340631 N/A N/A  4071  4086 TGGCCTTACCAGAATT 462325 1340634 N/A N/A  7127  7142 GACATGAAGATTAGTT  3 2326 1340638 N/AN/A  9727  9742 CTGTGAGAGGATAGTG 33 2327 1340645 1352 1367 21167 21182ATTCTGTGGCATGGCT 69 2328 1340668 2242 2257 22057 22072 CCATGCAAAAGCATTC72 2329 1340701 N/A N/A  3544  3559 AATCGCTGCTTAGTTC 41 2330 1340740 N/AN/A 19999 20014 CAGTTTTCCTCATGAT 65 2331 1340777 N/A N/A 14195 14210ATGTGATTGAGTTCTC 36 2332 1340783 N/A N/A  9915  9930 CTATCTCCCTATTTGT 152333 1340821 N/A N/A  7942  7957 GATCCATATTCCCTGA 74 2334 1340822 N/AN/A  5281  5296 CTGAGCTAGACAATTG 56 2335 1340832 N/A N/A  8668  8683TGTATGAGGTCTCTCA 66 2336 1340873 N/A N/A  6221  6236 CCAAACTTGCCCATAA 452337 1340879 N/A N/A  5161  5176 AGAGCCAAACTGCTAC 55 2338 1340894 N/AN/A  9372  9387 TAGAACACTTGCCTCA 31 2339 1340895 N/A N/A  9953  9968GAGTTCTACACCACAC 76 2340 1340901 N/A N/A 16332 16347 CTACTTCACTATATTG 332341 1340902 N/A N/A  6628  6643 GCTGTACAGTAGGCAG 66 2342 1340910 N/AN/A 12722 12737 GATTAATTCCCTTCCA 30 2343

TABLE 33Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2 SEQ Compound StartStop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′)Inhibition NO 1245927 N/A N/A  3433  3448 AGTAGATGGTAAGTCA 85  1211246023 N/A N/A  5046  5061 GAGTGAATCATTCAGT 79 1526 1340100 N/A N/A19467 19482 CTGGAAGGAGGATTCA 39 2344 1340117 N/A N/A 12419 12434GTAACGGTGATCAAAT 34 2345 1340119 N/A N/A  9971  9986 TTGAGTAGTGTAAGCT 522346 1340123 N/A N/A  9602  9617 ACATATGTGAAGAGCT 66 2347 1340127 11851200 21000 21015 CAGAAGTTTTTAAGAG 30 2348 1340135 N/A N/A 19847 19862GAACCTATGTGTGCAC 53 2349 1340145 N/A N/A  6391  6406 CTTGATGATTCTGACT 572350 1340189 N/A N/A 20479 20494 TAGTGGACTTCATTAG 52 2351 1340190 N/AN/A 14921 14936 CTATAATACATTAGCA  3 2352 1340193 N/A N/A 14618 14633CCCGAATTATTTCTTG 34 2353 1340196 N/A N/A 16225 16240 CTCTTTTTATAGACTG 632354 1340205 N/A N/A 19586 19601 GTAAACTAAAGTACTT  0 2355 1340212 N/AN/A 10930 10945 ATAAGGCCGATTCATG 38 2356 1340218 N/A N/A 20001 20016ATCAGTTTTCCTCATG 48 2357 1340228 N/A N/A 20361 20376 CTAAATTATTGCCTGA 392358 1340229* N/A N/A 20685 20700 GAAGAAACCTGTACAA 85 2359 1340234 N/AN/A 16337 16352 ATTAACTACTTCACTA 14 2360 1340238 N/A N/A 11855 11870TAAGCAGAATTGTGAA 35 2361 1340244 N/A N/A 16968 16983 CCAATATATACTGACA 682362 1340246 N/A N/A 13959 13974 GTCTACCTCTAAGTTA  3 2363 1340258 N/AN/A 11570 11585 CTTGACAATGGTTGAT 54 2364 1340266 N/A N/A 18748 18763AATATATACCTGTTGC 38 2365 1340271 N/A N/A 17990 18005 TTAGTATAGTTATCTT 372366 1340309 N/A N/A 14196 14211 TATGTGATTGAGTTCT 28 2367 1340311 N/AN/A 18178 18193 CTCGCGAGATGATGTT 40 2368 1340339 N/A N/A  6467  6482TAGGCAGTAAAGTGCT 48 2369 1340345 N/A N/A 18092 18107 TGATACACCAATGCAG 442370 1340348 N/A N/A  5283  5298 AACTGAGCTAGACAAT 44 2371 1340349 N/AN/A  6225  6240 TGTACCAAACTTGCCC 53 2372 1340354 N/A N/A  9148  9163ATGCCAAGCTTTGTGT 50 2373 1340357 N/A N/A  3375  3390 GTTGGAAGATGTATAC 532374 1340402 N/A N/A  9958  9973 GCTGAGAGTTCTACAC 45 2375 1340406 N/AN/A  8594  8609 TAAAGGTGGGATAAAC  0 2376 1340428 N/A N/A  9921  9936AATTCACTATCTCCCT 10 2377 1340440 1360 1375 21175 21190 TTGTTGATATTCTGTG52 2378 1340449 N/A N/A  5198  5213 TGAACCGTATTCCCAA 76 2379 1340466 N/AN/A  6638  6653 TTGGTTGGAGGCTGTA 60 2380 1340492 N/A N/A 15497 15512GCTGCATTAATGCCAC 46 2381 1340501 N/A N/A  6742  6757 TGCAATGAGATTACCC 542382 1340504 N/A N/A 12500 12515 CAGAAATTCACCTTGA 28 2383 1340505 N/AN/A  6302  6317 TCTAGGAGATATAACA 48 2384 1340506 N/A N/A 12758 12773GAGAATTGTTTAGTTC 47 2385 1340548 N/A N/A  5715  5730 CCAGATTGCACAAACC 722386 1340553 N/A N/A 10188 10203 TGCCAACACTAATCTC 30 2387 1340571 N/AN/A  9498  9513 TGGAAGATTAATCATA 12 2388 1340582 2243 2258 22058 22073TCCATGCAAAAGCATT 62 2389 1340626 N/A N/A  5657  5672 AAGTTACCAGAGCATT 702390 1340653 N/A N/A  5984  5999 GGATACCTGAAAAGCC 68 2391 1340655  701 716 12119 12134 GCAGAGACATGAGGTT 55 2392 1340657 N/A N/A  4076  4091TTTCATGGCCTTACCA 52 2393 1340678 N/A N/A  7130  7145 TTGGACATGAAGATTA 182394 1340692 N/A N/A  3756  3771 AGGCACTAAAGGTTTC 61 2395 1340693 N/AN/A  4476  4491 GGACAAATGCCTGAGA 52 2396 1340695 N/A N/A 13689 13704GTTTACTCACTTCTGG 29 2397 1340716 N/A N/A  8168  8183 GAGTTATTGTAGGGAT 692398 1340723 N/A N/A  8669  8684 TTGTATGAGGTCTCTC 50 2399 1340750 N/AN/A  7682  7697 GAAATTTGTGAACCTG 32 2400 1340759 N/A N/A  9755  9770CTACCTCCAAATTCCC 27 2401 1340763 N/A N/A  7947  7962 GAAGTGATCCATATTC 442402 1340786 N/A N/A 12890 12905 TCTTTAGTCAACAGTA 68 2403 1340788 N/AN/A 18667 18682 CTGGGATACTATTCTC 57 2404 1340800 N/A N/A 14388 14403TAGGCTTAGTGTAGAA 38 2405 1340805 N/A N/A  9319  9334 CCAAGTAATTACTTCT 682406 1340807 1471 1486 21286 21301 AAGGAAGAGGCTAGGG 57 2407 1340808 N/AN/A  5804  5819 TCCCCTCAAATAGCCT 60 2408 1340823 N/A N/A 20119 20134TTACAGCATCAAGACA 46 2409 1340842 N/A N/A 16124 16139 AATAATAGCTCTATTG  02410 1340846 N/A N/A  8981  8996 TGTCCAGAAGTATGTG  0 2411 1340857 N/AN/A  5162  5177 AAGAGCCAAACTGCTA 63 2412 1340859 N/A N/A  3568  3583TCAACCTGCACACCAT 72 2413 1340893 N/A N/A  5876  5891 GTAGGCTAAACCCTGG 622414 1340896 N/A N/A 11290 11305 ATGTTTTGATCCAGGG 46 2415 1340898 17201735 21535 21550 TTGTCTAAACATCTCT 60 2416 1340899 N/A N/A  3679  3694CATCCCCTAAGTTATT 24 2417 1340904 N/A N/A  9381  9396 CCATGGATCTAGAACA 152418 1340905 N/A N/A 10345 10360 CGTTAGGTTTCCAAAT  0 2419 1340908 N/AN/A  5048  5063 TAGAGTGAATCATTCA 75 2420

TABLE 34Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2 SEQ Compound StartStop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′)Inhibition NO 1245927 N/A N/A  3433  3448 AGTAGATGGTAAGTCA 88  1211246023 N/A N/A  5046  5061 GAGTGAATCATTCAGT 86 1526 1340080 N/A N/A10970 10985 TAATCTTGAGGCAGGA 17 2421 1340088 N/A N/A 12420 12435GGTAACGGTGATCAAA 51 2422 1340111 N/A N/A  9519  9534 TCTACACTAATATTGA 212423 1340121 N/A N/A 14619 14634 CCCCGAATTATTTCTT 35 2424 1340132 N/AN/A 16379 16394 CAACCAAACTTCCAGC 72 2425 1340133 N/A N/A 12502 12517TGCAGAAATTCACCTT 54 2426 1340160 N/A N/A  8675  8690 CTTCTATTGTATGAGG 402427 1340175 N/A N/A 11866 11881 TCTTACATGATTAAGC 35 2428 1340198 N/AN/A 15019 15034 TAAAATAGGGTGCAGT 58 2429 1340199 N/A N/A 20120 20135ATTACAGCATCAAGAC 63 2430 1340200 N/A N/A 14197 14212 TTATGTGATTGAGTTC 342431 1340222  734  749 12152 12167 ATTTTTGGTGAACCCA  8 2432 1340243 N/AN/A 13690 13705 CGTTTACTCACTTCTG 21 2433 1340259 N/A N/A 16126 16141ATAATAATAGCTCTAT  1 2434 1340261 1197 1212 21012 21027 TTTATGTAAGCACAGA70 2435 1340264 2247 2262 22062 22077 ATAGTCCATGCAAAAG 43 2436 13402691371 1386 21186 21201 ATTCTGTGTTCTTGTT 67 2437 1340280 N/A N/A 1799318008 AAGTTAGTATAGTTAT 20 2438 1340303 N/A N/A 17014 17029TAGCAATTTAGCAAGA 54 2439 1340307 N/A N/A 11571 11586 TCTTGACAATGGTTGA 752440 1340318 N/A N/A 19607 19622 TATTATGCACTCTATA  9 2441 1340338 N/AN/A 18672 18687 TTTTACTGGGATACTA 27 2442 1340347 N/A N/A  9924  9939TTGAATTCACTATCTC 45 2443 1340358 N/A N/A  5199  5214 TTGAACCGTATTCCCA 762444 1340363 N/A N/A  9975  9990 ACAGTTGAGTAGTGTA 72 2445 1340396 N/AN/A 20002 20017 AATCAGTTTTCCTCAT 53 2446 1340400 N/A N/A 20483 20498TTCATAGTGGACTTCA 51 2447 1340418 N/A N/A 20378 20393 CACAAGTAAGGTAAAG 542448 1340425 N/A N/A  6747  6762 CTAGTTGCAATGAGAT 65 2449 1340431 N/AN/A 10199 10214 GGTAAGCCCCATGCCA 38 2450 1340437 N/A N/A 11307 11322CACAAGCACACTGTAA  2 2451 1340455 N/A N/A  5716  5731 GCCAGATTGCACAAAC 602452 1340462 N/A N/A 16262 16277 GCAGAGACAGTAGATT 63 2453 1340470 N/AN/A  6228  6243 TTATGTACCAAACTTG 53 2454 1340493 N/A N/A  5985  6000AGGATACCTGAAAAGC 81 2455 1340508 N/A N/A 14392 14407 AACATAGGCTTAGTGT 182456 1340510 N/A N/A  4103  4118 ATCCTGTAAACACTTC 79 2457 1340513 N/AN/A  7949  7964 AGGAAGTGATCCATAT 60 2458 1340518 N/A N/A  9004  9019AGGCAAAGATCTGGCC  7 2459 1340519 N/A N/A  9386  9401 GCACCCCATGGATCTA 352460 1340524 1544 1559 21359 21374 TTCAGAGTTATACAGA 66 2461 1340527 N/AN/A  3680  3695 CCATCCCCTAAGTTAT 14 2462 1340544 1022 1037 20837 20852CTTTGCAGCATTGATT 47 2463 1340561 N/A N/A  3782  3797 GAACTGTGTTGCTTGT 772464 1340570 N/A N/A 19887 19902 TACGACAGGTCATCTT 58 2465 1340572 N/AN/A  6426  6441 ATGGTAAACTGTATGC 78 2466 1340575 N/A N/A  9606  9621ATTCACATATGTGAAG  0 2467 1340588 N/A N/A  4481  4496 TTTTTGGACAAATGCC 502468 1340609 N/A N/A  7683  7698 AGAAATTTGTGAACCT 39 2469 1340620 N/AN/A 18963 18978 ATGCAAGATTTACTTC 38 2470 1340640 N/A N/A  5049  5064TTAGAGTGAATCATTC 69 2471 1340642 N/A N/A  6308  6323 TGCTACTCTAGGAGAT 602472 1340648 N/A N/A  5809  5824 CAGTATCCCCTCAAAT 53 2473 1340650 17221737 21537 21552 AATTGTCTAAACATCT 62 2474 1340670 N/A N/A  8170  8185CAGAGTTATTGTAGGG 83 2475 1340680 N/A N/A  5169  5184 ATTGCATAAGAGCCAA 672476 1340687  519  534 10405 10420 GAAGAAGTGCTTTTGT 50 2477 1340691 N/AN/A  9757  9772 AGCTACCTCCAAATTC  0 2478 1340700 N/A N/A 14077 14092AACAACCCAGCCTCGG 20 2479 1340711 N/A N/A  9959  9974 AGCTGAGAGTTCTACA 672480 1340717 N/A N/A  3569  3584 ATCAACCTGCACACCA 63 2481 1340742 N/AN/A 19472 19487 TATAACTGGAAGGAGG 44 2482 1340744 N/A N/A 12780 12795TCAAATGAGGCGGCAC 46 2483 1340749 N/A N/A  6710  6725 GGAATGCTCATATTAA 192484 1340753 N/A N/A 15498 15513 TGCTGCATTAATGCCA 15 2485 1340756 N/AN/A  5284  5299 TAACTGAGCTAGACAA 53 2486 1340765 N/A N/A  9152  9167GTACATGCCAAGCTTT 61 2487 1340778 N/A N/A  6468  6483 ATAGGCAGTAAAGTGC 562488 1340828 N/A N/A  8600  8615 CTGTCATAAAGGTGGG 59 2489 1340840 N/AN/A  9320  9335 TCCAAGTAATTACTTC 72 2490 1340843 N/A N/A 18505 18520CTAATTTAGTCAACTT 40 2491 1340848 N/A N/A  5658  5673 TAAGTTACCAGAGCAT 772492 1340861 N/A N/A  3429  3444 GATGGTAAGTCAAATA 85 2493 1340871 N/AN/A  7426  7441 TTGGCCGAGGAGGGCG  3 2494 1340909 N/A N/A 13548 13563TCTAAAGGGCTGCTCT 33 2495 1340913 N/A N/A  5883  5898 CGCTACTGTAGGCTAA 682496 1340916 N/A N/A 18094 18109 ATTGATACACCAATGC 66 2497

TABLE 35Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2 SEQ Compound StartStop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′)Inhibition NO 1245927 N/A N/A  3433  3448 AGTAGATGGTAAGTCA 84  1211246023 N/A N/A  5046  5061 GAGTGAATCATTCAGT 81 1526 1340081 1028 104320843 20858 ATAAAGCTTTGCAGCA 54 2498 1340090 N/A N/A  9961  9976TAAGCTGAGAGTTCTA 64 2499 1340106 N/A N/A 19473 19488 CTATAACTGGAAGGAG 432500 1340110 N/A N/A 17228 17243 TGTACAAATTTATGCC 67 2501 1340114  565 580 10451 10466 GAAGCCACTGTGACGA 58 2502 1340118 N/A N/A  9608  9623CAATTCACATATGTGA 11 2503 1340128 N/A N/A 14461 14476 AGGTATGTCATACTTC  52504 1340143 N/A N/A 15021 15036 GATAAAATAGGGTGCA 52 2505 1340150 N/AN/A 15501 15516 ATTTGCTGCATTAATG 20 2506 1340165 N/A N/A 14198 14213ATTATGTGATTGAGTT 46 2507 1340177 N/A N/A  3682  3697 GCCCATCCCCTAAGTT 332508 1340185 N/A N/A 14621 14636 TGCCCCGAATTATTTC  3 2509 1340191 N/AN/A 19890 19905 GCTTACGACAGGTCAT 73 2510 1340195 N/A N/A 16127 16142CATAATAATAGCTCTA 41 2511 1340210 N/A N/A 18969 18984 TGACTAATGCAAGATT 452512 1340223 N/A N/A 13729 13744 TTAAGTACTGTGAGAC 35 2513 1340254 N/AN/A 13563 13578 GTTCAACTGAACCTCT 55 2514 1340265 N/A N/A 11897 11912TGAGAGTATAAATGGC 67 2515 1340272 N/A N/A 11576 11591 TATTCTCTTGACAATG 472516 1340294 N/A N/A 19651 19666 TTCTATGCAAGCCTTC 51 2517 1340300 N/AN/A 17998 18013 TTATGAAGTTAGTATA 31 2518 1340302 N/A N/A 18509 18524GACACTAATTTAGTCA 11 2519 1340319 2248 2263 22063 22078 GATAGTCCATGCAAAA64 2520 1340322  735  750 12153 12168 GATTTTTGGTGAACCC 30 2521 1340336N/A N/A  9925  9940 ATTGAATTCACTATCT 31 2522 1340372 N/A N/A  5988  6003GCAAGGATACCTGAAA 67 2523 1340373 N/A N/A  6309  6324 CTGCTACTCTAGGAGA 662524 1340379 N/A N/A 18095 18110 AATTGATACACCAATG 55 2525 1340382 N/AN/A  3570  3585 TATCAACCTGCACACC 62 2526 1340384 N/A N/A 18673 18688ATTTTACTGGGATACT 49 2527 1340394 N/A N/A 12503 12518 TTGCAGAAATTCACCT 362528 1340401 N/A N/A  5664  5679 AGAGCATAAGTTACCA 88 2529 1340404 N/AN/A  9977  9992 AGACAGTTGAGTAGTG 63 2530 1340414 N/A N/A  7954  7969AAACTAGGAAGTGATC 39 2531 1340422 N/A N/A  5202  5217 TTTTTGAACCGTATTC 562532 1340429 N/A N/A 16275 16290 CAGCAAAGTTTGGGCA 37 2533 1340434 N/AN/A 20121 20136 GATTACAGCATCAAGA 52 2534 1340435 N/A N/A  3784  3799TAGAACTGTGTTGCTT 78 2535 1340482 1199 1214 21014 21029 TGTTTATGTAAGCACA74 2536 1340496 N/A N/A  8605  8620 GAACACTGTCATAAAG 43 2537 1340499 N/AN/A 20380 20395 ATCACAAGTAAGGTAA 62 2538 1340500 N/A N/A 16380 16395CCAACCAAACTTCCAG 70 2539 1340526 N/A N/A 10974 10989 ATTGTAATCTTGAGGC 392540 1340529 N/A N/A  9158  9173 CTCCTGGTACATGCCA 47 2541 1340538 N/AN/A  6428  6443 TAATGGTAAACTGTAT 32 2542 1340584 N/A N/A  6748  6763CCTAGTTGCAATGAGA 77 2543 1340587 N/A N/A 12422 12437 GTGGTAACGGTGATCA 492544 1340590 N/A N/A  6711  6726 GGGAATGCTCATATTA 18 2545 1340594 N/AN/A  9057  9072 TGTCAGAGACTCTGTG 39 2546 1340607 N/A N/A  7708  7723CGTCCTAGGAAACAAA 45 2547 1340619 N/A N/A  8236  8251 CTACATGACCTGGGTC 592548 1340630 N/A N/A  4133  4148 GGAGTACTTCACAATT 79 2549 1340646 N/AN/A  5170  5185 GATTGCATAAGAGCCA 82 2550 1340654 N/A N/A  5810  5825TCAGTATCCCCTCAAA 64 2551 1340677 N/A N/A  8706  8721 GGACCAATATAATCCA 202552 1340706 N/A N/A  9323  9338 ACATCCAAGTAATTAC 56 2553 1340731 N/AN/A  5717  5732 TGCCAGATTGCACAAA 54 2554 1340737 N/A N/A 20486 20501AACTTCATAGTGGACT 68 2555 1340741 N/A N/A 14165 14180 GCAAGCCAACAGAGAG 522556 1340748 N/A N/A 11384 11399 TTTAGTCAGGTAGAGT 30 2557 1340751 N/AN/A  9411  9426 TGTATAGCTGCATTTC 37 2558 1340772 N/A N/A  5886  5901TTTCGCTACTGTAGGC 62 2559 1340780 N/A N/A  5054  5069 CAGCCTTAGAGTGAAT 822560 1340782 N/A N/A  4537  4552 GAGATTTGAAGGTTAG 82 2561 1340804 N/AN/A 20005 20020 AGTAATCAGTTTTCCT 65 2562 1340811 1546 1561 21361 21376ACTTCAGAGTTATACA 35 2563 1340815 N/A N/A  7473  7488 CATTCGGCTAGGCGCG 462564 1340816 N/A N/A  9759  9774 CAAGCTACCTCCAAAT 25 2565 1340817 13721387 21187 21202 CATTCTGTGTTCTTGT 60 2566 1340820 N/A N/A  3432  3447GTAGATGGTAAGTCAA 86 2567 1340826 1723 1738 21538 21553 AAATTGTCTAAACATC24 2568 1340847 N/A N/A  6246  6261 ACTGGATGGATTTCTC 83 2569 1340854 N/AN/A 10201 10216 ATGGTAAGCCCCATGC 22 2570 1340855 N/A N/A  6471  6486GTAATAGGCAGTAAAG 77 2571 1340866 N/A N/A 12794 12809 AAGAGTCAGTATCCTC 632572 1340877 N/A N/A  9521  9536 ATTCTACACTAATATT  0 2573 1340880 N/AN/A  5285  5300 ATAACTGAGCTAGACA 71 2574

TABLE 36Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2 SEQ Compound StartStop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′)Inhibition NO 1245927 N/A N/A  3433  3448 AGTAGATGGTAAGTCA 89  1211246023 N/A N/A  5046  5061 GAGTGAATCATTCAGT 91 1526 1340087 N/A N/A11578 11593 GTTATTCTCTTGACAA 42 2575 1340089 N/A N/A 11388 11403AACTTTTAGTCAGGTA 49 2576 1340116 N/A N/A 16381 16396 CCCAACCAAACTTCCA 622577 1340124  603  618 10489 10504 ATGGGATGAGGTAAGG 46 2578 1340136 N/AN/A 13782 13797 ACAATCAGGAGTTGCA 62 2579 1340153 N/A N/A  5223  5238TTAGCTTAAACTCCAA 78 2580 1340162 N/A N/A 12504 12519 CTTGCAGAAATTCACC 402581 1340188 N/A N/A 19489 19504 CATCTAGAATTAAGGG 53 2582 1340203 N/AN/A 18690 18705 CTTTGAGACTCTTGTT 61 2583 1340207 N/A N/A 18002 18017AGGCTTATGAAGTTAG 57 2584 1340216 N/A N/A 18971 18986 GTTGACTAATGCAAGA 592585 1340225 N/A N/A 18096 18111 AAATTGATACACCAAT 14 2586 1340227 N/AN/A 19891 19906 TGCTTACGACAGGTCA 81 2587 1340232 N/A N/A 19656 19671ATCCATTCTATGCAAG 46 2588 1340240 1397 1412 21212 21227 AAACTTGATCTCTTAG61 2589 1340248 1726 1741 21541 21556 CTAAAATTGTCTAAAC 35 2590 1340262N/A N/A 12423 12438 GGTGGTAACGGTGATC 31 2591 1340281 N/A N/A 20122 20137TGATTACAGCATCAAG 69 2592 1340285 2249 2264 22064 22079 GGATAGTCCATGCAAA64 2593 1340293 1597 1612 21412 21427 TCTTATAAGACTATAA 17 2594 1340299N/A N/A 14905 14920 AGCTAAGAGACACTTC 41 2595 1340313 N/A N/A 13568 13583GAACAGTTCAACTGAA 10 2596 1340326 1054 1069 20869 20884 TATTATCAGGACTGAA63 2597 1340328 N/A N/A 20382 20397 TAATCACAAGTAAGGT 54 2598 1340331 N/AN/A  8707  8722 GGGACCAATATAATCC 31 2599 1340351 N/A N/A  9194  9209ACAACCCTTAACAAAC 26 2600 1340371 N/A N/A  6479  6494 CCAACTATGTAATAGG 682601 1340378 N/A N/A  9982  9997 TATTAAGACAGTTGAG 44 2602 1340407 N/AN/A  4140  4155 TTCTCAAGGAGTACTT 76 2603 1340417 N/A N/A  9422  9437TATATGAGGTCTGTAT 42 2604 1340436 N/A N/A  9765  9780 CCAACCCAAGCTACCT 152605 1340441 N/A N/A  5812  5827 AGTCAGTATCCCCTCA 82 2606 1340442 N/AN/A  5718  5733 CTGCCAGATTGCACAA 44 2607 1340485 N/A N/A  5058  5073ATTACAGCCTTAGAGT 56 2608 1340486 N/A N/A  3571  3586 CTATCAACCTGCACAC 392609 1340487 N/A N/A  6749  6764 GCCTAGTTGCAATGAG 61 2610 1340509 N/AN/A  7476  7491 TAACATTCGGCTAGGC 52 2611 1340511 N/A N/A  3933  3948CTGCGCACATATTTTA 92 2612 1340516 N/A N/A  5667  5682 TAGAGAGCATAAGTTA 592613 1340523 N/A N/A  9927  9942 TGATTGAATTCACTAT N.D. 2614 1340536 N/AN/A 11924 11939 CCAAAAATCAGCCACT 0 2615 1340550 N/A N/A  7768  7783GCAGCTAAAATCCAAT 70 2616 1340557 N/A N/A 17672 17687 AACCTTTGTTGCCTGG 362617 1340559 N/A N/A 14462 14477 GAGGTATGTCATACTT 29 2618 1340562 N/AN/A 15510 15525 TATTCCAGGATTTGCT 43 2619 1340564 N/A N/A  3435  3450TAAGTAGATGGTAAGT 74 2620 1340581 N/A N/A  8613  8628 GGCCAAGGGAACACTG 362621 1340589 1200 1215 21015 21030 ATGTTTATGTAAGCAC 70 2622 1340591 N/AN/A  3693  3708 ATCCCGTTCTTGCCCA 30 2623 1340593 N/A N/A 12169 12184CCTTACCTTGTGCTTG 20 2624 1340595 N/A N/A  8017  8032 ATCTCACAAGGGAAAT 732625 1340596 N/A N/A  6435  6450 CTAGTGGTAATGGTAA 62 2626 1340602 N/AN/A 10206 10221 TTGGTATGGTAAGCCC 62 2627 1340605 N/A N/A  5286  5301TATAACTGAGCTAGAC 53 2628 1340621 N/A N/A  9327  9342 ATATACATCCAAGTAA 182629 1340622 N/A N/A  6247  6262 CACTGGATGGATTTCT 72 2630 1340641 N/AN/A  5176  5191 AGTTTAGATTGCATAA 50 2631 1340644 N/A N/A 16282 16297TAGTCTTCAGCAAAGT 49 2632 1340652 N/A N/A 14168 14183 ATAGCAAGCCAACAGA 372633 1340675 N/A N/A 14201 14216 ATTATTATGTGATTGA 39 2634 1340682 N/AN/A  9525  9540 CTAGATTCTACACTAA 17 2635 1340688 N/A N/A  9629  9644TAGTTTGGTGGGCATG 28 2636 1340699 N/A N/A 20487 20502 TAACTTCATAGTGGAC 762637 1340707 N/A N/A 16130 16145 CTCCATAATAATAGCT 59 2638 1340710 N/AN/A  9962  9977 GTAAGCTGAGAGTTCT 49 2639 1340736 N/A N/A  4640  4655TACGACTTCCTTCTAA 67 2640 1340774 N/A N/A 15212 15227 CCATAAAGCTGGATTG 402641 1340779 N/A N/A  5992 6007 AGAGGCAAGGATACCT 78 2642 1340797 N/A N/A18517 18532 AGTACCAAGACACTAA 66 2643 1340814 N/A N/A  8237  8252ACTACATGACCTGGGT 54 2644 1340818 N/A N/A  9077  9092 ACTTGAATTCTGTGTC 522645 1340849 N/A N/A  6316  6331 GACCATGCTGCTACTC 74 2646 1340853 N/AN/A 10978 10993 CAGCATTGTAATCTTG 43 2647 1340858 N/A N/A  6715  6730GCCAGGGAATGCTCAT 38 2648 1340860 N/A N/A 12796 12811 GTAAGAGTCAGTATCC 472649 1340886 N/A N/A  5888  5903 TATTTCGCTACTGTAG 48 2650 1340887 N/AN/A 20009 20024 AGAGAGTAATCAGTTT 39 2651

TABLE 37Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2 SEQ Compound StartStop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′)Inhibition NO 1245927 N/A N/A  3433  3448 AGTAGATGGTAAGTCA 83  1211246023 N/A N/A  5046  5061 GAGTGAATCATTCAGT 76 1526 1340073 N/A N/A12797 12812 TGTAAGAGTCAGTATC 43 2652 1340074 1203 1218 21018 21033AGTATGTTTATGTAAG 48 2653 1340084 N/A N/A 18692 18707 GACTTTGAGACTCTTG 652654 1340091 N/A N/A  9333 9348 GATCCTATATACATCC 49 2655 1340101 N/A N/A11391 11406 TGCAACTTTTAGTCAG 41 2656 1340103 N/A N/A 16383 16398ATCCCAACCAAACTTC 15 2657 1340140 605 620 10491 10506 ATATGGGATGAGGTAA 372658 1340159 N/A N/A  6029  6044 TTCCGTCTCACAATCT 79 2659 1340174 N/AN/A 13571 13586 TCAGAACAGTTCAACT 30 2660 1340178 1598 1613 21413 21428ATCTTATAAGACTATA 32 2661 1340202 N/A N/A 19658 19673 GAATCCATTCTATGCA 472662 1340217 N/A N/A 11579 11594 AGTTATTCTCTTGACA 48 2663 1340236 N/AN/A 20491 20506 GACATAACTTCATAGT 39 2664 1340237 N/A N/A 16131 16146GCTCCATAATAATAGC 21 2665 1340250 N/A N/A 12170 12185 ACCTTACCTTGTGCTT  02666 1340252 N/A N/A 18518 18533 TAGTACCAAGACACTA 27 2667 1340253 N/AN/A 18003 18018 AAGGCTTATGAAGTTA 61 2668 1340317 N/A N/A 18098 18113TGAAATTGATACACCA 58 2669 1340376 N/A N/A  5304  5319 CGGCCTATTCTTCTGT 252670 1340389 N/A N/A  7478  7493 ATTAACATTCGGCTAG 17 2671 1340392 N/AN/A 19498 19513 AATATCAGCCATCTAG 24 2672 1340410 1074 1089 20889 20904TGCCAAACCAATGTTT 32 2673 1340413 N/A N/A  9195  9210 GACAACCCTTAACAAA 242674 1340447 N/A N/A  3436  3451 ATAAGTAGATGGTAAG 58 2675 1340461 N/AN/A 17676 17691 TCAAAACCTTTGTTGC  6 2676 1340463 N/A N/A  6716  6731TGCCAGGGAATGCTCA 23 2677 1340464 N/A N/A  9647  9662 ATGTATGAGGTCTCCG 632678 1340477 N/A N/A 13824 13839 ACCAAGAGGGTTTTTA  7 2679 1340495 N/AN/A  4648  4663 ATTTTTAATACGACTT 35 2680 1340497 N/A N/A  9963  9978TGTAAGCTGAGAGTTC 45 2681 1340507 N/A N/A  9766  9781 CCCAACCCAAGCTACC 222682 1340517 N/A N/A 18983 18998 CACTTTGGTATTGTTG 53 2683 1340528 N/AN/A  8636  8651 GACTGTTGAGCTCAAA 52 2684 1340537 N/A N/A  5669  5684AGTAGAGAGCATAAGT 52 2685 1340540 N/A N/A  8040  8055 GACTACATTAACACCA 582686 1340541 N/A N/A  6438  6453 AAACTAGTGGTAATGG 47 2687 1340568 N/AN/A 20123 20138 CTGATTACAGCATCAA 40 2688 1340573 N/A N/A  6762  6777CTTGAGAGTGATTGCC 64 2689 1340579 2250 2265 22065 22080 AGGATAGTCCATGCAA64 2690 1340592 N/A N/A 10218 10233 GATACAAATTTATTGG 33 2691 1340598 N/AN/A  5720  5735 CACTGCCAGATTGCAC 38 2692 1340608 N/A N/A  3575  3590CTTTCTATCAACCTGC 68 2693 1340615 N/A N/A 14475 14490 AGTATGACAACTGGAG 152694 1340616 N/A N/A 20046 20061 CGTAACCATGCATTAA 68 2695 1340618 N/AN/A  6248  6263 CCACTGGATGGATTTC 68 2696 1340624 N/A N/A  7772  7787GTTAGCAGCTAAAATC 45 2697 1340635 N/A N/A  5814  5829 AAAGTCAGTATCCCCT 772698 1340649 N/A N/A  4222  4237 TCAACTAAACATGACA 77 2699 1340660 N/AN/A  9933  9948 GAATCATGATTGAATT 39 2700 1340672 N/A N/A  3695  3710AGATCCCGTTCTTGCC 68 2701 1340676 N/A N/A  5182  5197 CGCAACAGTTTAGATT 572702 1340703 N/A N/A  14911 14926 TTAGCAAGCTAAGAGA 42 2703 1340708 N/AN/A 12424 12439 GGGTGGTAACGGTGAT 46 2704 1340712 N/A N/A  3952  3967CAAGGAAAAGCCTGAC 59 2705 1340715 N/A N/A  8256  8271 CTGGTTTCATAACCTA  92706 1340718 N/A N/A  9423  9438 TTATATGAGGTCTGTA 32 2707 1340730 N/AN/A  8709  8724 TTGGGACCAATATAAT 18 2708 1340738 N/A N/A 11965 11980TGTGAGAAGGCGGTAT 20 2709 1340743 N/A N/A  5890  5905 TGTATTTCGCTACTGT 762710 1340754 N/A N/A 16284 16299 AATAGTCTTCAGCAAA 48 2711 1340758 N/AN/A 19904 19919 AAGATACCCAGGTTGC 59 2712 1340784 N/A N/A  5226  5241GCTTTAGCTTAAACTC 72 2713 1340787 N/A N/A  9081  9096 GTCCACTTGAATTCTG 182714 1340799 N/A N/A  5066  5081 TGAGTTACATTACAGC 90 2715 1340825 17481763 21563 21578 GTGTTAGCTTTAATTT 48 2716 1340844 1398 1413 21213 21228GAAACTTGATCTCTTA 64 2717 1340851 N/A N/A  9528  9543 GCCCTAGATTCTACAC 152718 1340868 N/A N/A 15214 15229 TTCCATAAAGCTGGAT  5 2719 1340869 N/AN/A 11073 11088 TACAACCTGGTTTCAT 25 2720 1340881 N/A N/A  6321  6336AGGGAGACCATGCTGC 79 2721 1340888 N/A N/A  6480  6495 ACCAACTATGTAATAG 472722 1340890 N/A N/A 14204 14219 CAGATTATTATGTGAT 51 2723 1340900 N/AN/A  9989 10004 GTAACTGTATTAAGAC 54 2724 1340906 N/A N/A 12506 12521TTCTTGCAGAAATTCA 42 2725 1340912 N/A N/A 14169 14184 AATAGCAAGCCAACAG  92726 1340914 N/A N/A 20384 20399 AGTAATCACAAGTAAG 54 2727 1340915  794 809 15675 15690 ATCTATCAGACTTCTT 47 2728

TABLE 38Inhibition of HSD17B13 RNA by 3-10-3 cEt gapmers targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: 1 1 2 2 SEQ Compound StartStop Start Stop % ID Number Site Site Site Site Sequence (5′ to 3′)Inhibition NO 1245927 N/A N/A  3433  3448 AGTAGATGGTAAGTCA 84  1211246023 N/A N/A  5046  5061 GAGTGAATCATTCAGT 91 1526 1340076 N/A N/A12426 12441 CAGGGTGGTAACGGTG 55 2729 1340079 N/A N/A 12191 12206ACCCATTCTAACTTGA  0 2730 1340105 N/A N/A 13825 13840 TACCAAGAGGGTTTTT 172731 1340107 N/A N/A 12798 12813 CTGTAAGAGTCAGTAT 42 2732 1340112 N/AN/A 20493 20508 TTGACATAACTTCATA 15 2733 1340115 N/A N/A 12003 12018TGTTAGCTAAGGGAGA  0 2734 1340139 N/A N/A 17768 17783 CAGCATATTCATTTGG 492735 1340147 N/A N/A  5831  5846 TGTTAGGACCCAGTCT 51 2736 1340161 N/AN/A  6764  6779 TTCTTGAGAGTGATTG 52 2737 1340167 N/A N/A  4659  4674GCCCTTAAGTCATTTT 25 2738 1340173 N/A N/A 11075 11090 ATTACAACCTGGTTTC 502739 1340184 N/A N/A 14913 14928 CATTAGCAAGCTAAGA  0 2740 1340186 N/AN/A 13576 13591 CACTATCAGAACAGTT 24 2741 1340214 N/A N/A 14173 14188CTTGAATAGCAAGCCA 25 2742 1340219 N/A N/A 18519 18534 TTAGTACCAAGACACT 412743 1340224 N/A N/A 20109 20124 AAGACATTCTAGCCTG 63 2744 1340242 N/AN/A 12616 12631 ATGGCTTAATTTTCGG 33 2745 1340251 N/A N/A 20190 20205AGTTATTAGAAGTCAG 54 2746 1340257 N/A N/A 20386 20401 ATAGTAATCACAAGTA 562747 1340267 1749 1764 21564 21579 TGTGTTAGCTTTAATT 38 2748 1340296 N/AN/A 14476 14491 GAGTATGACAACTGGA 23 2749 1340298  808  823 15689 15704TTGGTAAGTATTCCAT 20 2750 1340316 1175 1190 20990 21005 TAAGAGGCATGAAAGG52 2751 1340325 N/A N/A  8713  8728 AGTTTTGGGACCAATA 31 2752 1340343 N/AN/A 11580 11595 GAGTTATTCTCTTGAC 57 2753 1340344 N/A N/A  7479  7494AATTAACATTCGGCTA 38 2754 1340365 N/A N/A 16384 16399 AATCCCAACCAAACTT 232755 1340374 N/A N/A 19673 19688 CAAGAGACACCACCAG 50 2756 1340381 N/AN/A  6439  6454 TAAACTAGTGGTAATG 14 2757 1340383 N/A N/A  5894  5909CCTTTGTATTTCGCTA 47 2758 1340408 N/A N/A  6326  6341 TTCATAGGGAGACCAT 652759 1340421 N/A N/A  9964  9979 GTGTAAGCTGAGAGTT 60 2760 1340424 N/AN/A 10499 10514 ACTTACCAATATGGGA  0 2761 1340457 N/A N/A 15247 15262ATAGCTAAGTATACTT  0 2762 1340480 N/A N/A 18102 18117 ATACTGAAATTGATAC 112763 1340481 N/A N/A  9651  9666 GCTAATGTATGAGGTC 78 2764 1340483 N/AN/A  9112  9127 AGACCAAGTAGCTTAC 42 2765 1340488 N/A N/A  5070  5085GATCTGAGTTACATTA 69 2766 1340502 N/A N/A  9999 10014 GAAATCTTGTGTAACT 692767 1340535 N/A N/A  9198  9213 ACTGACAACCCTTAAC 10 2768 1340551 N/AN/A 16285 16300 GAATAGTCTTCAGCAA 51 2769 1340569 N/A N/A  8050  8065TTCTACAGAAGACTAC 40 2770 1340583 N/A N/A  9432  9447 ACTAACCAATTATATG  62771 1340611 N/A N/A 16132 16147 TGCTCCATAATAATAG 35 2772 1340623 16031618 21418 21433 AATGTATCTTATAAGA 10 2773 1340632 N/A N/A 18998 19013AGTCATATTGAAAATC 39 2774 1340637 N/A N/A  7773  7788 AGTTAGCAGCTAAAAT 332775 1340639 N/A N/A  5185  5200 CAACGCAACAGTTTAG 52 2776 1340656 N/AN/A 10258 10273 AGCATTCCATGATTAA 47 2777 1340658 N/A N/A 18005 18020CCAAGGCTTATGAAGT 27 2778 1340662 N/A N/A  8279  8294 TCTAAAGTGCTGGTTG 342779 1340663 N/A N/A  6482  6497 GCACCAACTATGTAAT 53 2780 1340666 N/AN/A  3697  3712 TCAGATCCCGTTCTTG 59 2781 1340702 N/A N/A  3584  3599CTCCTGAGTCTTTCTA 23 2782 1340714 N/A N/A  5227  5242 TGCTTTAGCTTAAACT 512783 1340720 N/A N/A 19531 19546 GCTAAAATGGTCATCT 40 2784 1340721 23562371 22171 22186 TTTATAACTACAAGAG 38 2785 1340732 N/A N/A  8639  8654ACAGACTGTTGAGCTC 53 2786 1340733 1254 1269 21069 21084 TTTTGTCCACCTTTAA68 2787 1340735 N/A N/A  9334  9349 CGATCCTATATACATC 33 2788 1340745 N/AN/A  9767  9782 TCCCAACCCAAGCTAC  8 2789 1340760 N/A N/A 19905 19920TAAGATACCCAGGTTG 39 2790 1340764 N/A N/A  3478  3493 GACCAGGGAATTTATC 412791 1340766 N/A N/A  9934  9949 TGAATCATGATTGAAT 38 2792 1340793 N/AN/A  5646  5661 GCATTCATCAGATGTT 89 2793 1340794 N/A N/A  6717  6732CTGCCAGGGAATGCTC 23 2794 1340796 N/A N/A  6033  6048 ACTTTTCCGTCTCACA 892795 1340806 N/A N/A  5671  5686 TCAGTAGAGAGCATAA 52 2796 1340809 14171432 21232 21247 TGAGATAAAGCTGCCT 63 2797 1340827 N/A N/A  5732  5747TGGTAGCTTGCTCACT 71 2798 1340829 N/A N/A  6249  6264 GCCACTGGATGGATTT 362799 1340856 N/A N/A 11392 11407 CTGCAACTTTTAGTCA 21 2800 1340862 N/AN/A  9530  9545 CTGCCCTAGATTCTAC 33 2801 1340867 N/A N/A 14263 14278GAGTTAGGGAGCCAGC 39 2802 1340882 N/A N/A  4223  4238 TTCAACTAAACATGAC 552803 1340897 N/A N/A 18693 18708 AGACTTTGAGACTCTT 57 2804 1340911 N/AN/A  3988  4003 GTTTACAAGTAAGAAC 42 2805

Modified oligonucleotides complementary to an HSD17B13 nucleic acid withother chemistry modifications were synthesized and tested for theireffect on HSD17B13 RNA levels in vitro, as described above. TheChemistry Notation column in the Tables below specifies the chemistry ofeach modified oligonucleotide; wherein subscript ‘d’ represents a2′-β-D-deoxyribosyl sugar moiety, subscript ‘e’ represents a 2′-MOEsugar moiety, subscript ‘y’ represents a 2′-O-methyl sugar moiety,subscript ‘k’ represents a cEt modified sugar moiety, subscript ‘s’represents a phosphorothioate internucleoside linkage, and superscript‘m’ before the cytosine residue represents a 5-methyl cytosine.

TABLE 39Inhibition of HSD17B13 RNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound StartStop Start Stop Sequence Chemistry Notation % ID Number Site Site SiteSite (5' to 3') (5' to 3') Inhibition NO 1245927 N/A N/A  3433  3448AGTAGATGGTAAGTCA A_(ks)G_(ks)T_(ks)A_(ds)G_(ds)A_(ds)T_(ds)G_(ds)G_(ds)78  121 T_(ds)A_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1246023 N/A N/A 5046  5061 GAGTGAATCATTCAGTG_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds)A_(ds)T_(ds) ^(m) 78 1526C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)T_(k) 1341171  700  71512118 12133 CAGAGACATGAGGTTT ^(m)C_(ks)A_(ks)G_(ds)A_(ds)G_(ds)A_(ds)^(m)C_(ds)A_(ds) 61 2319 T_(ds)G_(ds)A_(ds)G_(ks)G_(es)T_(ks)T_(es)T_(k)1341175  794  809 15675 15690 ATCTATCAGACTTCTT A_(ks)T_(ks)^(m)C_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)A_(ds) 37 2728 G_(ds)A_(ds)^(m)C_(ds)T_(ks)T_(es) ^(m)C_(ks)T_(es)T_(k) 1341179  606  621 1049210507 AATATGGGATGAGGTAA_(ks)A_(ks)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds)A_(ds) 52 1424T_(ds)G_(ds)A_(ks)G_(es)G_(ks)T_(es)A_(k) 1341180 1080 1095 20895 20910TGCTAGTGCCAAACCA T_(ks)G_(ks) ^(m)C_(ds)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds)^(m) 58 1432 C_(ds) ^(m)C_(ds)A_(ds)A_(ks)A_(es) ^(m)C_(ks)^(m)C_(es)A_(k) 1341189 1019 1034 20834 20849 TGCAGCATTGATTCGAT_(ks)G_(ks) ^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) 42 419T_(ds)G_(ds)A_(ds)T_(ks)T_(es) ^(m)C_(ks)G_(es)A_(k) 1341190 1258 127321073 21088 TAGCTTTTGTCCACCT T_(ks)A_(ks)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) 71 1900 T_(ds) ^(m)C_(ds)^(m)C_(ks)A_(es) ^(m)C_(ks) ^(m)C_(es)T_(k) 1341193 1202 1217 2101721032 GTATGTTTATGTAAGCG_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)T_(ds)T_(ds)A_(ds) 72 1511T_(ds)G_(ds)T_(ks)A_(es)A_(ks)G_(es) ^(m)C_(k) 1341198 1084 1099 2089920914 CTGCTGCTAGTGCCAA ^(m)C_(ks)T_(ks)G_(ds) ^(m)C_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds) 44 1743 A_(ds)G_(ds)T_(ds)G_(ks) ^(m)C_(es)^(m)C_(ks)A_(es)A_(k) 1341200 1316 1331 21131 21146 AACAGTCTTAAACCTTA_(ks)A_(ks) ^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds) 37  188T_(ds)A_(ds)A_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks)T_(es)T_(k) 1341213 13241339 21139 21154 GCTACTTGAACAGTCT G_(ks) ^(m)C_(ks)T_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)G_(ds) 64  811 A_(ds)A_(ds)^(m)C_(ds)A_(ks)G_(es)T_(ks) ^(m)C_(es)T_(k) 1341217 1312 1327 2112721142 GTCTTAAACCTTCCCT G_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds) ^(m) 28 1901 C_(ds)^(m)C_(ds)T_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(es)T_(k) 13412281333 1348 21148 21163 GATTGGAATGCTACTTG_(ks)A_(ks)T_(ds)T_(ds)G_(ds)G_(ds)A_(ds)A_(ds)T_(ds) 53 1435 G_(ds)^(m)C_(ds)T_(ks)A_(es) ^(m)C_(ks)T_(es)T_(k) 1341234 1356 1371 2117121186 TGATATTCTGTGGCAT T_(ks)G_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ds) 46 1124 G_(ds)T_(ds)G_(ks)G_(es) ^(m)C_(ks)A_(es)T_(k)1341236 1352 1367 21167 21182 ATTCTGTGGCATGGCT A_(ks)T_(ks)T_(ds)^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds) 55 2328^(m)C_(ds)A_(ds)T_(ks)G_(es)G_(ks) ^(m)C_(es)T_(k) 1341239 1340 135521155 21170 GGCTACAGATTGGAAT G_(ks)G_(ks) ^(m)C_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds)G_(ds) 73 1980A_(ds)T_(ds)T_(ds)G_(ks)G_(es)A_(ks)A_(es)T_(k) 1341241 1387 1402 2120221217 TCTTAGCTGTGCACTC T_(ks) ^(m)C_(ks)T_(ds)T_(ds)A_(ds)G_(ds)^(m)C_(ds)T_(ds)G 50  190 _(ds)T_(ds)G_(ds) ^(m)C_(ks)A_(es)^(m)C_(ks)T_(es) ^(m)C_(k) 1341247 1364 1379 21179 21194GTTCTTGTTGATATTC G_(ks)T_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)G_(ds)T_(ds)T_(ds) 66 1436G_(ds)A_(ds)T_(ks)A_(es)T_(ks)T_(es) ^(m)C_(k) 1341250 1393 1408 2120821223 TTGATCTCTTAGCTGT T_(ks)T_(ks)G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds) 38  658 T_(ds)T_(ds)A_(ds)G_(ks) ^(m)C_(es)T_(ks)G_(es)T_(k)1341258 1420 1435 21235 21250 GGTTGAGATAAAGCTGG_(ks)G_(ks)T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)A_(ds)T_(ds) 60 1826A_(ds)A_(ds)A_(ks)G_(es) ^(m)C_(ks)T_(es)G_(k) 1341263 1489 1504 2130421319 CGTTTTGGGCTAATGA^(m)C_(ks)G_(ks)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)G_(ds) 37 1282^(m)C_(ds)T_(ds)A_(ks)A_(es)T_(ks)G_(es)A_(k) 1341267 1493 1508 2130821323 GCACCGTTTTGGGCTA G_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds)^(m)C_(ds)G_(ds)T_(ds)T_(ds) 49 1593 T_(ds)T_(ds)G_(ds)G_(ks)G_(es)^(m)C_(ks)T_(es)A_(k) 1341274 1497 1512 21312 21327 AGTTGCACCGTTTTGGA_(ks)G_(ks)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m) 41 1905C_(ds)G_(ds)T_(ds)T_(ks)T_(es)T_(ks)G_(es)G_(k) 1341280 1622 1637 2143721452 AGAGTCGGTCACCTTT A_(ks)G_(ks)A_(ds)G_(ds)T_(ds)^(m)C_(ds)G_(ds)G_(ds) 61  428 T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ks)^(m)C_(es)T_(ks)T_(es)T_(k)  1341281 1630 1645 21445 21460TTTAAAATAGAGTCGG T_(ks)T_(ks)T_(ds)A_(ds)A_(ds)A_(ds)A_(ds)T_(ds)A_(ds)43 1051 G_(ds)A_(ds)G_(ks)T_(es) ^(m)C_(ks)G_(es)G_(k) 1341287 1618 163321433 21448 TCGGTCACCTTTCATA T_(ks) ^(m)C_(ks)G_(ds)G_(ds)T_(ds)^(m)C_(ds)A_(ds) ^(m)C_(ds) 63 116 ^(m)C_(ds)T_(ds)T_(ds)T_(ks)^(m)C_(es)A_(ks)T_(es)A_(k) 1341290 1626 1641 21441 21456AAATAGAGTCGGTCAC A_(ks)A_(ks)A_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)50  740 ^(m)C_(ds)G_(ds)G_(ks)T_(es) ^(m)C_(ks)A_(es) ^(m)C_(k) 13412961714 1729 21529 21544 AAACATCTCTGGGACC A_(ks)A_(ks)A_(ds)^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m) 36 2129C_(ds)T_(ds)G_(ds)G_(ks)G_(es)A_(ks) ^(m)C_(es) ^(m)C_(k) 1341297 17101725 21525 21540 ATCTCTGGGACCAAGG A_(ks)T_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ds)G 65   37 _(ds)A_(ds) ^(m)C_(ds)^(m)C_(ks)A_(es)A_(ks)G_(es)G_(k) 1341303 1768 1783 21583 21598CCAGTACAGTTCCTTT ^(m)C_(ks) ^(m)C_(ks)A_(ds)G_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds) 75 1753 G_(ds)T_(ds)T_(ds) ^(m)C_(ks)^(m)C_(es)T_(ks)T_(es)T_(k) 1341305 1750 1765 21565 21580CTGTGTTAGCTTTAAT^(m)C_(ks)T_(ks)G_(ds)T_(ds)G_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 47 1286^(m)C_(ds)T_(ds)T_(ks)T_(es)A_(ks)A_(es)T_(k) 1341313 1778 1793 2159321608 TATGTAATAGCCAGTAT_(ks)A_(ks)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds) 78  508 G_(ds)^(m)C_(ds) ^(m)C_(ks)A_(es)G_(ks)T_(es)A_(k) 1341315 1782 1797 2159721612 TTCTTATGTAATAGCC T_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 78  819A_(ds)A_(ds)T_(ks)A_(es)G_(ks) ^(m)C_(es) ^(m)C_(k) 1341325 2247 226222062 22077 ATAGTCCATGCAAAAG A_(ks)T_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds) 31 2436 T_(ds)G_(ds)^(m)C_(ds)A_(ks)A_(es)A_(ks)A_(es)G_(k) 1341328 2193 2208 22008 22023TAGTCTTGATGTAGTG T_(ks)A_(ks)G_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) 43 1288T_(ds)G_(ds)T_(ks)A_(es)G_(ks)T_(es)G_(k) 1341339 N/A N/A  9330  9345CCTATATACATCCAAG ^(m)C_(ks)^(m)C_(ks)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m) 61 1771C_(ds)A_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)A_(es)G_(k) 1341343 N/AN/A 11571 11586 TCTTGACAATGGTTGA T_(ks)^(m)C_(ks)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds) 40 2440A_(ds)T_(ds)G_(ds)G_(ks)T_(es)T_(ks)G_(es)A_(k) 1341344 N/A N/A 1185511870 TAAGCAGAATTGTGAA T_(ks)A_(ks)A_(ds)G_(ds)^(m)C_(ds)A_(ds)G_(ds)A_(ds) 29 2361A_(ds)T_(ds)T_(ds)G_(ks)T_(es)G_(ks)A_(es)A_(k) 1341347 N/A N/A  9964 9979 GTGTAAGCTGAGAGTT G_(ks)T_(ks)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)^(m)C_(ds) 57 2760 T_(ds)G_(ds)A_(ds)G_(ks)A_(es)G_(ks)T_(es)T_(k)1341351 N/A N/A 12423 12438 GGTGGTAACGGTGATCG_(ks)G_(ks)T_(ds)G_(ds)G_(ds)T_(ds)A_(ds)A_(ds) ^(m) 39 2591C_(ds)G_(ds)G_(ds)T_(ks)G_(es)A_(ks)T_(es) ^(m)C_(k) 1341354 N/A N/A14914 14929 ACATTAGCAAGCTAAG A_(ks)^(m)C_(ks)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds) 23 2065A_(ds)A_(ds)G_(ds) ^(m)C_(ks)T_(es)A_(ks)A_(es)G_(k) 1341360 N/A N/A15494 15509 GCATTAATGCCACCCT G_(ks)^(m)C_(ks)A_(ds)T_(ds)T_(ds)A_(ds)A_(ds)T_(ds)G_(ds) 24 1012 ^(m)C_(ds)^(m)C_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(es)T_(k) 1341361 N/A N/A16287 16302 TAGAATAGTCTTCAGCT_(ks)A_(ks)G_(ds)A_(ds)A_(ds)T_(ds)A_(ds)G_(ds)T_(ds) 50 1403^(m)C_(ds)T_(ds)T_(ks) ^(m)C_(es)A_(ks)G_(es) ^(m)C_(k) 1341375 N/A N/A17992 18007 AGTTAGTATAGTTATCA_(ks)G_(ks)T_(ds)T_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds) 47 1249A_(ds)G_(ds)T_(ks)T_(es)A_(ks)T_(es) ^(m)C_(k) 1341377 N/A N/A 1638016395 CCAACCAAACTTCCAG ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ds) ^(m)c_(ds)^(m)C_(ds)A_(ds) 15 2539 A_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ks) ^(m)C_(es)^(m)C_(ks)A_(es)G_(k) 1341382 N/A N/A 19908 19923 TCTTAAGATACCCAGGT_(ks) ^(m)C_(ks)T_(ds)T_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds) 35  319A_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(es)G_(k) 1341387 N/A N/A18693 18708 AGACTTTGAGACTCTT A_(ks)G_(ks)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)A_(ds) 55 2804 G_(ds)A_(ds)^(m)C_(ks)T_(es) ^(m)C_(ks)T_(es)T_(k) 1341389 N/A N/A 19912 19927TGCATCTTAAGATACC T_(ks)G_(ks) ^(m)C_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds) 24 2050 A_(ds)A_(ds)G_(ds)A_(ks)T_(es)A_(ks)^(m)C_(es) ^(m)C_(k) 1341393 N/A N/A 20381 20396 AATCACAAGTAAGGTAA_(ks)A_(ks)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)A_(ds) 59 1333G_(ds)T_(ds)A_(ds)A_(ks)G_(es)G_(ks)T_(es)A_(k) 1341396 N/A N/A 2011620131 CAGCATCAAGACATTC ^(m)C_(ks)A_(ks)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)^(m)C_(ds)A_(ds) 62 2191 A_(ds)G_(ds)A_(ds) ^(m)C_(ks)A_(es)T_(ks)T_(es)^(m)C_(k) 1341406 N/A N/A 12503 12518 TTGCAGAAATTCACCTT_(ks)T_(ks)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)A_(ds)A_(ds) 46 2528A_(ds)T_(ds)T_(ds) ^(m)C_(ks)A_(es) ^(m)C_(ks) ^(m)C_(es)T_(k) 1341407N/A N/A 20482 20497 TCATAGTGGACTTCAT T_(ks)^(m)C_(ks)A_(ds)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 48  633 G_(ds)A_(ds)^(m)C_(ds)T_(ks)T_(es) ^(m)C_(ks)A_(es)T_(k) 1341412 N/A N/A 14196 14211TATGTGATTGAGTTCT T_(ks)A_(ks)T_(ds)G_(ds)T_(ds)G_(ds)A_(ds)T_(ds)T_(ds)23 2367 G_(ds)A_(ds)G_(ks)T_(es)T_(ks) ^(m)C_(es)T_(k) 1341415 N/A N/A13952 13967 TCTAAGTTAGCCCCCA T_(ks)^(m)C_(ks)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds) 19  928 G_(ds)^(m)C_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(es)A_(k) 1341417 N/AN/A 14170 14185 GAATAGCAAGCCAACA G_(ks)A_(ks)A_(ds)T_(ds)A_(ds)G_(ds)^(m)C_(ds)A_(ds) 27 1708 A_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(es)A_(ks)^(m)C_(es)A_(k) 1341532 805 820 15686 15701 GTAAGTATTCCATCTAG_(ks)T_(ks)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)T_(ds) 53 1038^(m)C_(ds) ^(m)C_(ds)A_(ks)T_(es) ^(m)C_(ks)T_(es)A_(k) 1341534 613 628N/A N/A CTGGAACAATATGGGA ^(m)C_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)^(m)C_(ds)A_(ds) 33 1969 A_(ds)T_(ds)A_(ds)T_(ks)G_(es)G_(ks)G_(es)A_(k)1341538 1091 1106 20906 20921 CGTTTGACTGCTGCTA^(m)C_(ks)G_(ks)T_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds) 48  264T_(ds)G_(ds) ^(m)C_(ds)T_(ks)G_(es) ^(m)C_(ks)T_(es)A_(k) 1341541 13201335 21135 21150 CTTGAACAGTCTTAAA^(m)C_(ks)T_(ks)T_(ds)G_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ds) 38  500G_(ds)T_(ds) ^(m)C_(ds)T_(ks)T_(es)A_(ks)A_(es)A_(k) 1341543 1308 132321123 21138 TAAACCTTCCCTGTGT T_(ks)A_(ks)A_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ds)T_(ds) ^(m)  9 1745 C_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ks)G_(es)T_(ks)G_(es)T_(k) 1341547 1076 1091 20891 20906AGTGCCAAACCAATGT A_(ks)G_(ks)T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds) 71 1120 A_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ks)A_(es)T_(ks)G_(es)T_(k) 1341551 1347 1362 21162 21177GTGGCATGGCTACAGA G_(ks)T_(ks)G_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)59  501 G_(ds) ^(m)C_(ds)T_(ds)A_(ks) ^(m)C_(es)A_(ks)G_(es)A_(k)1341555 1328 1343 21143 21158 GAATGCTACTTGAACAG_(ks)A_(ks)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds)A_(ds) ^(m) 48 1123C_(ds)T_(ds)T_(ds)G_(ks)A_(es)A_(ks) ^(m)C_(es)A_(k) 1341564 1425 144021240 21255 GTCCAGGTTGAGATAA G_(ks)T_(ks) ^(m)C_(ds)^(m)C_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 36  113T_(ds)G_(ds)A_(ds)G_(ks)A_(es)T_(ks)A_(es)A_(k) 1341565 1461 1476 2127621291 CTAGGGAAATCTTTCA^(m)C_(ks)T_(ks)A_(ds)G_(ds)G_(ds)G_(ds)A_(ds)A_(ds) 46  659A_(ds)T_(ds) ^(m)C_(ds)T_(ks)T_(es)T_(ks) ^(m)C_(es)A_(k) 1341567 14151430 21230 21245 AGATAAAGCTGCCTGCA_(ks)G_(ks)A_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds) ^(m) 30 1515C_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks)G_(es) ^(m)C_(k) 13415681718 1733 21533 21548 GTCTAAACATCTCTGG G_(ks)T_(ks)^(m)C_(ds)T_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ds) 50  429 A_(ds)T_(ds)^(m)C_(ds)T_(ks) ^(m)C_(es)T_(ks)G_(es)G_(k) 1341569 1504 1519 2131921334 AGAATAGAGTTGCACCA_(ks)G_(ks)A_(ds)A_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 59  426T_(ds)T_(ds)G_(ks) ^(m)C_(es)A_(ks) ^(m)C_(es) ^(m)C_(k) 1341575 16141629 21429 21444 TCACCTTTCATAATGT T_(ks) ^(m)C_(ks)A_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 31 2109^(m)C_(ds)A_(ds)T_(ds)A_(ks)A_(es)T_(ks)G_(es)T_(k) 1341578 2186 220122001 22016 GATGTAGTGGGAGTCGG_(ks)A_(ks)T_(ds)G_(ds)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 38  743G_(ds)G_(ds)A_(ks)G_(es)T_(ks) ^(m)C_(es)G_(k) 1341580 2257 2272 2207222087 AAACAAGAGGATAGTC A_(ks)A_(ks)A_(ds)^(m)C_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 52  744G_(ds)G_(ds)A_(ds)T_(ks)A_(es)G_(ks)T_(es) ^(m)C_(k) 1341585 1774 178921589 21604 TAATAGCCAGTACAGT T_(ks)A_(ks)A_(ds)T_(ds)A_(ds)G_(ds)^(m)C_(ds) ^(m)C_(ds) 44  196 A_(ds)G_(ds)T_(ds)A_(ks)^(m)C_(es)A_(ks)G_(es)T_(k) 1341588 N/A N/A  9511  9526 AATATTGAGGCACTGGA_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds)A_(ds)G_(ds) 29 1538 G_(ds)^(m)C_(ds)A_(ks) ^(m)C_(es)T_(ks)G_(es)G_(k) 1341596 N/A N/A  9598  9613ATGTGAAGAGCTGGTA A_(ks)T_(ks)G_(ds)T_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ds)54  527 G_(ds) ^(m)C_(ds)T_(ks)G_(es)G_(ks)T_(es)A_(k) 1341603 N/A N/A16134 16149 GATGCTCCATAATAAT G_(ks)A_(ks)T_(ds)G_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds) ^(m)C_(ds) 17 2049A_(ds)T_(ds)A_(ds)A_(ks)T_(es)A_(ks)A_(es)T_(k) 1341604 N/A N/A 1612416139 AATAATAGCTCTATTG A_(ks)A_(ks)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)G_(ds)^(m)  2 2410 C_(ds)T_(ds) ^(m)C_(ds)T_(ks)A_(es)T_(ks)T_(es)G_(k)1341614 N/A N/A 17987 18002 GTATAGTTATCTTCTCG_(ks)T_(ks)A_(ds)T_(ds)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds) 49  937 T_(ds)^(m)C_(ds)T_(ks)T_(es) ^(m)C_(ks)T_(es) ^(m)C_(k) 1341615 N/A N/A 1799718012 TATGAAGTTAGTATAGT_(ks)A_(ks)T_(ds)G_(ds)A_(ds)A_(ds)G_(ds)T_(ds)T_(ds) 47 1560A_(ds)G_(ds)T_(ks)A_(es)T_(ks)A_(es)G_(k)

TABLE 40 Inhibition of HSD17B13 RNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: % SEQ Compound 1 Start1 Stop 2 Start 2 Stop Sequence Chemistry Notation in- ID Number SiteSite Site Site (5′ to 3′) (5′ to 3′) hibition NO 1245927 N/A N/A 34333448 AGTAGATGGTAAGTCAA_(ks)G_(ks)T_(ks)A_(ds)G_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 76 121T_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1246023 N/A N/A 5046 5061GAGTGAATCATTCAGT G_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds) 84 1526 A_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)T_(k)1341176  796  811 15677 15692 CCATCTATCAGACTTC ^(m)C_(ks)^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)T_(ds) 52 415^(m)C_(ds)A_(ds)G_(ds)A_(ks) ^(m)C_(es)T_(ks)T_(es) ^(m)C_(k) 1341182 808  823 15689 15704 TTGGTAAGTATTCCATT_(ks)T_(ks)G_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds) 13 2750A_(ds)T_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)T_(k) 1341183 1077 109220892 20907 TAGTGCCAAACCAATG T_(ks)A_(ks)G_(ds)T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds) 66 1198 A_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ks)A_(es)A_(ks)T_(es)G_(k) 1341187 1081 1096 20896 20911CTGCTAGTGCCAAACC ^(m)C_(ks)T_(ks)G_(ds)^(m)C_(ds)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 51 1510 ^(m) _(k)CA_(s) ^(m)_(k)CA_(s)A_(ks)A_(es)A_(ks) ^(m)C_(es) ^(m)C_(k) 1341191 1085 110020900 20915 ACTGCTGCTAGTGCCA A_(ks) ^(m)C_(ks)T_(ds)G_(ds)^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds) 39 1821 T_(ds)A_(ds)G_(ds)T_(ks)G_(es)^(m)C_(ks) ^(m)C_(es)A_(k) 1341202 1259 1274 21074 21089GTAGCTTTTGTCCACC G_(ks)T_(ks)A_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 34 1978 G_(ds)T_(ds) ^(m)C_(ks)^(m)C_(es)A_(ks) ^(m)C_(es) ^(m)C_(k) 1341204 1313 1328 21128 21143AGTCTTAAACCTTCCC A_(ks)G_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds) 43 1979 ^(m)C_(ds)^(m)C_(ds)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(k) 1341211 1325 134021140 21155 TGCTACTTGAACAGTC T_(ks)G_(ks) ^(m)C_(ds)T_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)G_(ds) 64 889 A_(ds)A_(ds)^(m)C_(ks)A_(es)G_(ks)T_(es) ^(m)C_(k) 1341214 1321 1336 21136 21151ACTTGAACAGTCTTAA A_(ks) ^(m)C_(ks)T_(ds)T_(ds)G_(ds)A_(ds)A_(ds)^(m)C_(ds) 60 578 A_(ds)G_(ds)T_(ds) ^(m)C_(ks)T_(es)T_(ks)A_(es)A_(k)1341218 1317 1332 21132 21147 GAACAGTCTTAAACCT G_(ks)A_(ks)A_(ds)^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) 63 266T_(ds)T_(ds)A_(ds)A_(ks)A_(es) ^(m)C_(ks) ^(m)C_(es)T_(k) 1341222 13421357 21157 21172 ATGGCTACAGATTGGA A_(ks)T_(ks)G_(ds)G_(ds)^(m)C_(ds)T_(ds)A_(ds) ^(m)C_(ds) 57 111A_(ds)G_(ds)A_(ds)T_(ks)T_(es)G_(ks)G_(es)A_(k) 1341226 1329 1344 2114421159 GGAATGCTACTTGAAC G_(ks)G_(ks)A_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)A_(d) 49 1201 _(s)^(m)C_(ds)T_(ds)T_(ks)G_(es)A_(ks)A_(es) ^(m)C_(k) 1341227 1335 135021150 21165 CAGATTGGAATGCTAC^(m)C_(ks)A_(ks)G_(ds)A_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(d) 57 1590_(s)A_(ds)T_(ds)G_(ks) ^(m)C_(es)T_(ks)A_(es) ^(m)C_(k) 1341237 13531368 21168 21183 TATTCTGTGGCATGGC T_(ks)A_(ks)T_(ds)T_(ds)^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 57 890 G_(ds)^(m)C_(ds)A_(ks)T_(es)G_(ks)G_(es) ^(m)C_(k) 1341242 1366 1381 2118121196 GTGTTCTTGTTGATAT G_(ks)T_(ks)G_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)G_(ds) 63 1514T_(ds)T_(ds)CT_(ks)A_(es)T_(ks)A_(e)T_(k) 1341248 1357 1372 21172 21187TTGATATTCTGTGGCA T_(ks)T_(ks)G_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)^(M)C_(ds) 55 1202 T_(ds)G_(ds)T_(ks)G_(es)G_(ks) ^(m)C_(es)A_(k)1341254 1421 1436 21236 21251 AGGTTGAGATAAAGCTA_(ks)G_(ks)G_(ds)T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)A_(ds) 60 1904T_(ds)A_(ds)A_(ks)A_(es)G_(ks) ^(m)C_(es)T_(k) 1341262 1490 1505 2130521320 CCGTTTTGGGCTAATG ^(m)C_(ks)^(m)C_(ks)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G 72 1360 _(ds)G_(ds)^(m)C_(ds)T_(ks)A_(es)A_(ks)T_(es)G_(k) 1341265 1494 1509 21309 21324TGCACCGTTTTGGGCT T_(ks)G_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds)G_(ds)T_(ds) 29 1671 T_(ds)T_(ds)T_(ds)G_(ks)G_(es)G_(ks)^(m)C_(es)T_(k) 1341269 1464 1479 21279 21294 AGGCTAGGGAAATCTTA_(ks)G_(ks)G_(ds) ^(m)C_(ds)T_(ds)A_(ds)G_(ds)G_(ds)G_(d) 45 892_(s)A_(ds)A_(ds)A_(ks)T_(es) ^(m)C_(ks)T_(es)T_(k) 1341275 1619 163421434 21449 GTCGGTCACCTTTCAT G_(ks)T_(ks) ^(m)C_(ds)G_(ds)G_(ds)T_(ds)^(m)C_(ds)A_(ds) ^(m) 57 194 C_(ds) ^(m)C_(ds)T_(ds)T_(ks)T_(es)^(m)C_(ks)A_(es)T_(k) 1341277 1598 1613 21413 21428 ATCTTATAAGACTATAA_(ks)T_(ks) ^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)A_(ds) 30 2661G_(ds)A_(ds) ^(m)C_(ks)T_(es)A_(ks)T_(es)A_(k) 1341284 1627 1642 2144221457 AAAATAGAGTCGGTCAA_(ks)A_(ks)A_(ds)A_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 53 817 T_(ds)^(m)C_(ds)G_(ks)G_(es)T_(ks) ^(m)C_(es)A_(k) 1341286 1623 1638 2143821453 TAGAGTCGGTCACCTT T_(ks)A_(ks)G_(ds)A_(ds)G_(ds)T_(ds)^(m)C_(ds)G_(ds)G_(ds) 48 506 T_(ds) ^(m)C_(ds)A_(ks) ^(m)C_(es)^(m)C_(ks)T_(es)T_(k) 1341291 1711 1726 21526 21541 CATCTCTGGGACCAAG^(m)C_(ks)A_(ks)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds) 44 117G_(ds)G_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)A_(es)G_(k) 1341292 17151730 21530 21545 TAAACATCTCTGGGAC T_(ks)A_(ks)A_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T 39 351 _(ds)^(m)C_(ds)T_(ds)G_(ks)G_(es)G_(ks)A_(es) ^(m)C_(k) 1341300 1719 173421534 21549 TGTCTAAACATCTCTG T_(ks)G_(ks)T_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)A_(ds) ^(m)C 59 507 _(ds)A_(ds)T_(ds)^(m)C_(ks)T_(es) ^(m)C_(ks)T_(es)G_(k) 1341302 1770 1785 21585 21600AGCCAGTACAGTTCCT A_(ks)G_(ks) ^(m)C_(ds)^(m)C_(ds)A_(ds)G_(ds)T_(ds)A_(ds) ^(m) 49 1909C_(ds)A_(ds)G_(ds)T_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es)T_(k) 1341307 17511766 21566 21581 CCTGTGTTAGCTTTAA ^(m)C_(ks)^(m)C_(ks)T_(ds)G_(ds)T_(ds)G_(ds)T_(ds)T_(ds)A 62 1364 _(ds)G_(ds)^(m)C_(ds)T_(ks)T_(es)T_(ks)A_(es)A_(k) 1341310 1783 1798 21598 21613TTTCTTATGTAATAGC T_(ks)T_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 60 2128T_(ds)A_(ds)A_(ks)T_(es)A_(ks)G_(es) ^(m)C_(k) 1341314 1779 1794 2159421609 TTATGTAATAGCCAGTT_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds) 63 586A_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)G_(es)T_(k) 1341316 1775 179021590 21605 GTAATAGCCAGTACAG G_(ks)T_(ks)A_(ds)A_(ds)T_(ds)A_(ds)G_(ds)^(m)C_(ds) ^(m) 47 274 C_(ds)A_(ds)G_(ds)T_(ks)A_(es)^(m)C_(ks)A_(es)G_(k) 1341329 2187 2202 22002 22017 TGATGTAGTGGGAGTCT_(ks)G_(ks)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)G_(ds)T_(ds) 46 820G_(ds)G_(ds)G_(ks)A_(es)G_(ks)T_(es) ^(m)C_(k) 1341332 N/A N/A 9514 9529ACTAATATTGAGGCAC A_(ks)^(m)C_(ks)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds) 27 1772G_(ds)A_(ds)G_(ks)G_(es) ^(m)C_(ks)A_(es) ^(m)C_(k) 1341334 2250 226522065 22080 AGGATAGTCCATGCAAA_(ks)G_(ks)G_(ds)A_(ds)T_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(d) 46 2690 _(s)^(m)C_(ds)A_(ds)T_(ks)G_(es) ^(m)C_(ks)A_(es)A_(k) 1341337 N/A N/A 93329347 ATCCTATATACATCCA A_(ks)T_(ks) ^(m)C_(ds)^(m)C_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T 65 1927 _(ds)A_(ds)^(m)C_(ds)A_(ks)T_(es) ^(m)C_(ks) ^(m)C_(es)A_(k) 1341342 N/A N/A 99669981 TAGTGTAAGCTGAGAGT_(ks)A_(ks)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 68 1852^(m)C_(ds)T_(ds)G_(ks)A_(es)G_(ks)A_(es)G_(k) 1341346 N/A N/A 9601 9616CATATGTGAAGAGCTG^(m)C_(ks)A_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)A_(d) 35 683_(s)A_(ds)G_(ds)A_(ks)G_(es) ^(m)C_(ks)T_(es)G_(k) 1341348 N/A N/A 1154811563 TCTCTTGACAATGGTT T_(ks) ^(m)C_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m) 70 1389 11573 11588C_(ds)A_(ds)A_(ds)T_(ks)G_(es)G_(ks)T_(es)T_(k) 100 1341350 N/A N/A14916 14931 ATACATTAGCAAGCTA A_(ks)T_(ks)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(d) 22 309 _(s)^(m)C_(ds)A_(ds)A_(ks)G_(es) ^(m)C_(ks)T_(es)A_(k) 1341358 N/A N/A 1419714212 TTATGTGATTGAGTTCT_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)A_(ds)T_(ds)T 21 2431_(ds)G_(ds)A_(ks)G_(es)T_(ks)T_(es) ^(m)C_(k) 1341363 N/A N/A 1549615511 CTGCATTAATGCCACC ^(m)C_(ks)T_(ks)G_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)A 6 1168 _(ds)T_(ds)G_(ds) ^(m)C_(ks)^(m)C_(es)A_(ks) ^(m)C_(es) ^(m)C_(k) 1341364 N/A N/A 16127 16142CATAATAATAGCTCTA^(m)C_(ks)A_(ks)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)A_(ds)T_(ds) 13 2511A_(ds)G_(ds) ^(m)C_(ks)T_(es)T_(ks) ^(m)C_(es)A_(k) 1341365 N/A N/A16289 16304 GTTAGAATAGTCTTCAG_(ks)T_(ks)T_(ds)A_(ds)G_(ds)A_(ds)A_(ds)T_(ds)A_(ds) 45 1481G_(ds)T_(ds) ^(m)C_(ks)T_(es)T_(ks) ^(m)C_(es)A_(k) 1341370 N/A N/A16382 16397 TCCCAACCAAACTTCC T_(ks) ^(m)C_(ks) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m) 27 2026 C_(ds)A_(ds)A_(ds)A_(ds)^(m)C_(ks)T_(es)T_(ks) ^(m)C_(es) ^(m) C_(k) 1341371 N/A N/A 18095 18110AATTGATACACCAATG A_(ks)A_(ks)T_(ds)Ta_(s)G_(ds)A_(ds)T_(ds)A_(ds)^(m)C_(ds) 50 2525 A_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(es)A_(ks)T_(es)G_(k)1341376 N/A N/A 17994 18009 GAAGTTAGTATAGTTAG_(ks)A_(ks)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds)G_(ds)T_(ds) 56 1327A_(ds)T_(ds)A_(ks)G_(es)T_(ks)T_(es)A_(k) 1341379 N/A N/A 17989 18004TAGTATAGTTATCTTC T_(ks)A_(ks)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)G_(ds)T_(ds)34 1093 T_(ds)A_(ds)T_(ks) ^(m)C_(es)T_(ks)T_(es) ^(m)C_(k) 1341380 N/AN/A 19909 19924 ATCTTAAGATACCCAG A_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds)G_(ds)A_(d) 45 397 _(s)T_(ds)A_(ds)^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)G_(k) 1341384 N/A N/A 19913 19928GTGCATCTTAAGATAC G_(ks)T_(ks)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds)T 20 2806 _(ds)A_(ds)A_(ds)G_(ks)A_(es)T_(ks)A_(es)^(m)C_(k) 1341388 N/A N/A 18695 18710 AAAGACTTTGAGACTCA_(ks)A_(ks)A_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(d) 45 1250_(s)G_(ds)A_(ds)G_(ks)A_(es) ^(m)C_(ks)T_(es) ^(m)C_(k) 1341391 N/A N/A20383 20398 GTAATCACAAGTAAGG G_(ks)T_(ks)A_(ds)A_(ds)T_(ds)^(m)C_(ds)A_(ds) ^(m)C_(ds) 72 1411A_(ds)A_(ds)G_(ds)T_(ks)A_(es)A_(ks)G_(es)G_(k) 1341399 N/A N/A 2019020205 AGTTATTAGAAGTCAGA_(ks)G_(ks)T_(ds)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 42 2746A_(ds)A_(ds)G_(ks)T_(es) ^(m)C_(ks)A_(es)G_(k) 1341401 N/A N/A 2048420499 CTTCATAGTGGACTTC ^(m)C_(ks)T_(ks)T_(ds)^(m)C_(ds)A_(ds)T_(ds)A_(ds)G_(ds)T 45 711 _(ds)G_(ds)G_(ds)A_(ks)^(m)C_(es)T_(ks)T_(es) ^(m)C_(k) 1341410 N/A N/A 13954 13969CCTCTAAGTTAGCCCC ^(m)C_(ks) ^(m)C_(ks)T_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 20 1084 T_(ds)T_(ds)A_(ds)G_(ks)^(m)C_(es) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(k) 1341418 N/A N/A 12797 12812TGTAAGAGTCAGTATC T_(ks)G_(ks)T_(ds)A_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)35 2652 ^(m)C_(ds)A_(ds)G_(ks)T_(es)A_(ks)T_(es) ^(m)C_(k) 1341419 N/AN/A 14172 14187 TTGAATAGCAAGCCAAT_(ks)T_(ks)G_(ds)A_(ds)A_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds) 27 1864A_(ds)A_(ds)G_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)A_(k) 1341529 693 70812111 12126 ATGAGGTTTTGATACCA_(ks)T_(ks)G_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds) 51 569T_(ds)G_(ds)A_(ks)T_(es)A_(ks) ^(m)C_(es) ^(m)C_(k) 1341533 1022 103720837 20852 CTTTGCAGCATTGATT ^(m)C_(ks)T_(ks)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds)G_(ds) ^(m) 49 2463C_(ds)A_(ds)T_(ds)T_(ks)G_(es)A_(ks)T_(es)T_(k) 1341540 1309 1324 2112421139 TTAAACCTTCCCTGTG T_(ks)T_(ks)A_(ds)A_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ds)T_(ds) 0 2807 ^(m)C_(ds) ^(m)C_(ds)^(m)C_(ks)T_(es)G_(ks)T_(es)G_(k) 1341545 1175 1190 20990 21005TAAGAGGCATGAAAGG T_(ks)A_(ks)A_(ds)G_(ds)A_(ds)G_(ds)G_(ds)^(m)C_(ds)A_(d) 54 2751 _(s)T_(ds)G_(ds)A_(ks)A_(es)A_(ks)G_(es)G_(k)1341546 1251 1266 21066 21081 TGTCCACCTTTAAATG T_(ks)G_(ks)T_(ds)^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(d) 27 1666_(s)T_(ds)T_(ds)T_(ds)A_(ks)A_(es)A_(ks)T_(es)G_(k) 1341552 1348 136321163 21178 TGTGGCATGGCTACAG T_(ks)G_(ks)T_(ds)G_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(d) 22 579 _(s)G_(ds) ^(m)C_(ds)T_(ks)A_(es)^(m)C_(ks)A_(es)G_(k) 1341554 1394 1409 21209 21224 CTTGATCTCTTAGCTG^(m)C_(ks)T_(ks)T_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m) 49 736C_(ds)T_(ds)T_(ds)A_(ks)G_(es) ^(m)C_(ks)T_(es)G_(k) 1341558 1388 140321203 21218 CTCTTAGCTGTGCACT ^(m)C_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds) 56 268T_(ds)G_(ds)T_(ds)G_(ks) ^(m)C_(es)A_(ks) ^(m)C_(es)T_(k) 1341560 14981513 21313 21328 GAGTTGCACCGTTTTG G_(ks)A_(ks)G_(ds)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds) ^(m) 61 1983 C_(ds)^(m)C_(ds)G_(ds)T_(ks)T_(es)T_(ks)T_(es)G_(k) 1341563 1416 1431 2123121246 GAGATAAAGCTGCCTGG_(ks)A_(ks)G_(ds)A_(ds)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds) ^(m) 40 1592C_(ds)T_(ds)G_(ks) ^(m)C_(es) ^(m)C_(ks)T_(es)G_(k) 1341566 1426 144121241 21256 TGTCCAGGTTGAGATA T_(ks)G_(ks)T_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)G_(ds)G_(ds)T 48 191_(ds)T_(ds)G_(ds)A_(ks)G_(es)A_(ks)T_(es)A_(k) 1341574 1615 1630 2143021445 GTCACCTTTCATAATG G_(ks)T_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ds)T_(ds) 4 1907 T_(ds)^(m)C_(ds)A_(ds)T_(ks)A_(es)A_(ks)T_(es)G_(k) 1341577 1705 1720 2152021535 TGGGACCAAGGATATA T_(ks)G_(ks)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds) 30 1674 A_(ds)G_(ds)G_(ds)A_(ks)T_(es)A_(ks)T_(es)A_(k)1341583 2194 2209 22009 22024 TTAGTCTTGATGTAGTT_(ks)T_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds) 36 1366A_(ds)T_(ds)G_(ks)T_(es)A_(ks)G_(es)T_(k) 1341589 N/A N/A 11858 11873GATTAAGCAGAATTGT G_(ks)A_(ks)T_(ds)T_(ds)A_(ds)A_(ds)G_(ds)^(m)C_(ds)A_(d) 31 1156 _(s)G_(ds)A_(ds)A_(ks)T_(es)T_(ks)G_(es)T_(k)1341591 N/A N/A 11543 11558 TGACAATGGTTGCCAC T_(ks)G_(ks)A_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 38 1233 T_(ds)T_(ds)G_(ks)^(m)C_(es) ^(m)C_(ks)A_(es) ^(m)C_(k) 1341595 2350 2365 22165 22180ACTACAAGAGGTTATT A_(ks) ^(m)C_(ks)T_(ds)A_(ds)^(m)C_(ds)A_(ds)A_(ds)G_(ds) 42 899A_(ds)G_(ds)G_(ds)T_(ks)T_(es)A_(ks)T_(es)T_(k) 1341600 N/A N/A 1241612431 ACGGTGATCAAATGTA A_(ks)^(m)C_(ks)G_(ds)G_(ds)T_(ds)G_(ds)A_(ds)T_(ds) ^(m) 33 2205C_(ds)A_(ds)A_(ds)A_(ks)T_(es)G_(ks)T_(es)A_(k) 1341601 N/A N/A 1621816233 TATAGACTGGGTAGGA T_(ks)A_(ks)T_(ds)A_(ds)G_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(d) 38 2808_(s)G_(ds)G_(ds)T_(ks)A_(es)G_(ks)G_(es)A_(k) 1341607 N/A N/A 1242612441 CAGGGTGGTAACGGTG^(m)C_(ks)A_(ks)G_(ds)G_(ds)G_(ds)T_(ds)G_(ds)G_(ds)T_(d) 49 2729_(s)A_(ds)A_(ds) ^(m)C_(ks)G_(es)G_(ks)T_(es)G_(k)

TABLE 41 Inhibition of HSD17B13 RNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: % SEQ Compound 1 Start1 Stop 2 Start 2 Stop Sequence Chemistry Notation in- ID Number SiteSite Site Site (5′ to 3′) (5′ to 3′) hibition NO 1245927 N/A N/A  3433 3448 AGTAGATGGTAAGTCAA_(ks)G_(ks)T_(ks)A_(ds)G_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(d) 93 121_(s)A_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1246023 N/A N/A  5046  5061GAGTGAATCATTCAGT G_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds) 88 1526 A_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)T_(k)1341165  608  623 N/A N/A ACAATATGGGATGAGG A_(ks)^(m)C_(ks)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 51 1579G_(ds)A_(ds)T_(ks)G_(es)A_(ks)G_(es)G_(k) 1341170  810  825 15691 15706TATTGGTAAGTATTCCT_(ks)A_(ks)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(d) 36 1272_(s)T_(ds)A_(ks)T_(es)T_(ks) ^(m)C_(es) ^(m)C_(k) 1341174  798  81315679 15694 TTCCATCTATCAGACT T_(ks)T_(ks) ^(m)C_(ds)^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(d) 33 571 _(s)T_(ds)^(m)C_(ds)A_(ks)G_(es)A_(ks) ^(m)C_(es)T_(k) 1341177  696  711 1211412129 GACATGAGGTTTTGAT G_(ks)A_(ks)^(m)C_(ds)A_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(ds) 55 647T_(ds)T_(ds)T_(ks)T_(es)G_(ks)A_(es)T_(k) 1341181 1078 1093 20893 20908CTAGTGCCAAACCAAT ^(m)C_(ks)T_(ks)A_(ds)G_(ds)T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ds)A 47 1276 _(ds)A_(ds)A_(ds) ^(m)C_(ks)^(m)C_(es)A_(ks)A_(es)T_(k) 1341185 1082 1097 20897 20912GCTGCTAGTGCCAAAC G_(ks) ^(m)C_(ks)T_(ds)G_(ds)^(m)C_(ds)T_(ds)A_(ds)G_(ds)T_(ds) 62 1587 G_(ds) ^(m)C_(ds)^(m)C_(kS)A_(eS)A_(kS)A_(es) ^(m)C_(k) 1341195 1180 1195 20995 21010GTTTTTAAGAGGCATGG_(ks)T_(ks)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 79 1199G_(ds)Gr_(ks) ^(m)C_(es)A_(ks)T_(es)G_(k) 1341197 1086 1101 20901 20916GACTGCTGCTAGTGCC G_(ks)A_(ks) ^(m)C_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)G_(ds) ^(m)C 35 1899 _(ds)T_(ds)A_(ds)G_(ks)T_(es)G_(ks)^(m)C_(es) ^(m)C_(k) 1341201 1314 1329 21129 21144 CAGTCTTAAACCTTCC^(m)C_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds) 51 30A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es)T_(ks) ^(m)C_(es) ^(m)C_(k) 13412061256 1271 21071 21086 GCTTTTGTCCACCTTT G_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 75 1744^(m)C_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks)T_(es)T_(k) 1341207 12611276 21076 21091 AGGTAGCTTTTGTCCA A_(ks)G_(ks)G_(ds)T_(ds)A_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T 26 109 _(ds)T_(ds)G_(ks)T_(es) ^(m)C_(ks)^(m)C_(es)A_(k) 1341210 1326 1341 21141 21156 ATGCTACTTGAACAGTA_(ks)T_(ks)G_(ds) ^(m)C_(ds)T_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ds) 54 967G_(ds)A_(ds)A_(ks) ^(m)C_(es)A_(ks)G_(es)T_(k) 1341212 1322 1337 2113721152 TACTTGAACAGTCTTA T_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds)A_(ds) ^(m)C_(ds) 60 656A_(ds)G_(ds)T_(ks) ^(m)C_(es)T_(ks)T_(es)A_(k) 1341219 1318 1333 2113321148 TGAACAGTCTTAAACC T_(ks)G_(ks)A_(ds)A_(ds)^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) 34 344T_(ds)T_(ds)A_(ks)A_(es)A_(ks) ^(m)C_(es) ^(m)C_(k) 1341225 1344 135921159 21174 GCATGGCTACAGATTG G_(ks) ^(m)C_(ks)A_(ds)T_(ds)G_(ds)G_(ds)^(m)C_(ds)T_(ds)A_(ds) 41 267^(m)C_(ds)A_(ds)G_(ks)A_(es)T_(ks)T_(es)G_(k) 1341231 1354 1369 2116921184 ATATTCTGTGGCATGG A_(ks)T_(ks)A_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ds)G_(ds)T_(ds)G 43 968 _(ds)G_(ds)^(m)C_(ks)A_(es)T_(ks)G_(es)G_(k) 1341233 1358 1373 21173 21188GTTGATATTCTGTGGC G_(ks)T_(ks)T_(ds)G_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)^(m)C 69 1280 _(ds)T_(ds)G_(ks)T_(es)G_(ks)G_(es) ^(m)C_(k) 1341238 13491364 21164 21179 CTGTGGCATGGCTACA^(m)C_(ks)T_(ks)G_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) 33 657G_(ds)G_(ds) ^(m)C_(ks)T_(es)A_(ks) ^(m)C_(es)A_(k) 1341240 1395 141021210 21225 ACTTGATCTCTTAGCT A_(ks)^(m)C_(ks)T_(ds)T_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) 62 813^(m)C_(ds)T_(ds)T_(ks)A_(es)G_(ks) ^(m)C_(es)T_(k) 1341243 1389 140421204 21219 TCTCTTAGCTGTGCAC T_(ks) ^(m)C_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(d) 36 346_(s)T_(ds)G_(ds)T_(ks)G_(es) ^(m)C_(ks)A_(es) ^(m)C_(k) 1341246 13671382 21182 21197 TGTGTTCTTGTTGATA T_(ks)G_(ks)T_(ds)G_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)G 64 1591 _(ds)T_(ds)T_(ks)G_(es)A_(ks)T_(es)A_(k)1341251 1429 1444 21244 21259 ATATGTCCAGGTTGAGA_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) 28 425G_(ds)G_(ds)T_(ks)T_(es)G_(ks)A_(es)G_(k) 1341257 1418 1433 21233 21248TTGAGATAAAGCTGCCT_(ks)T_(ks)G_(ds)A_(ds)G_(ds)A_(ds)T_(ds)A_(ds)A_(ds)A_(d) 2 1670_(s)G_(ds) ^(m)C_(ks)T_(es)G_(ks) ^(m)C_(es) ^(m)C_(k) 1341259 1422 143721237 21252 CAGGTTGAGATAAAGC^(m)C_(ks)A_(ks)G_(ds)G_(ds)T_(ds)T_(ds)G_(ds)A_(ds)G_(ds) 53 1982A_(ds)T_(ds)A_(ks)A_(es)A_(ks)G_(es) ^(m)C_(k) 1341260 1491 1506 2130621321 ACCGTTTTGGGCTAAT A_(ks) ^(m)C_(ks)^(m)C_(ds)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) 76 1438 G_(ds)G_(ds)^(m)C_(ks)T_(es)A_(ks)A_(es)T_(k) 1341261 1495 1510 21310 21325TTGCACCGTTTTGGGC T_(ks)T_(ks)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds)G_(ds)T_(d) 26 1749 _(s)T_(ds)T_(ds)T_(ks)G_(es)G_(ks)G_(es)^(m)C_(k) 1341268 1466 1481 21281 21296 AGAGGCTAGGGAAATCA_(ks)G_(ks)A_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ds)A_(ds)G_(ds) 59 1048G_(ds)G_(ds)A_(ks)A_(es)A_(ks)T_(es) ^(m)C_(k) 1341273 1499 1514 2131421329 AGAGTTGCACCGTTTT A_(ks)G_(ks)A_(ds)G_(ds)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds) ^(m) 80 34 C_(ds)^(m)C_(ds)G_(ks)T_(es)T_(ks)T_(es)T_(k) 1341279 1600 1615 21415 21430GTATCTTATAAGACTA G_(ks)T_(ks)A_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A 61 1595 _(ds)A_(ds)G_(ks)A_(es)^(m)C_(ks)T_(es)A_(k) 1341285 1624 1639 21439 21454 ATAGAGTCGGTCACCTA_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)G_(ds) 56 584G_(ds)T_(ds) ^(m)C_(ks)A_(es) ^(m)C_(ks) ^(m)C_(es)T_(k) 1341288 16201635 21435 21450 AGTCGGTCACCTTTCA A_(ks)G_(ks)T_(ds)^(m)C_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ds) 55 272 ^(m)C_(ds)^(m)C_(ds)T_(ks)T_(es)T_(ks) ^(m)C_(es)A_(k) 1341298 1712 1727 2152721542 ACATCTCTGGGACCAA A_(ks) ^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)G_(d) 67 195 _(s)G_(ds)G_(ds)A_(ks) ^(m)C_(es)^(m)C_(ks)A_(es)A_(k) 1341299 1628 1643 21443 21458 TAAAATAGAGTCGGTCT_(ks)A_(ks)A_(ds)A_(ds)A_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G 68 895_(ds)T_(ds) ^(m)C_(ks)G_(es)G_(ks)T_(es) ^(m)C_(k) 1341306 1721 173621536 21551 ATTGTCTAAACATCTC A_(ks)T_(ks)T_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)A 62 585 _(ds) ^(m)C_(ds)A_(ks)T_(es)^(m)C_(ks)T_(es) ^(m)C_(k) 1341308 1752 1767 21567 21582TCCTGTGTTAGCTTTA T_(ks) ^(m)C_(ks)^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds)T_(ds)T_(ds) 79 1442 A_(ds)G_(ds)^(m)C_(ks)T_(es)T_(ks)T_(es)A_(k) 1341312 1784 1799 21599 21614GTTTCTTATGTAATAG G_(ks)T_(ks)T_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)G 21 897_(ds)T_(ds)A_(ks)A_(es)T_(ks)A_(es)G_(k) 1341317 1780 1795 21595 21610CTTATGTAATAGCCAG^(m)C_(ks)T_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T 61 664_(ds)A_(ds)G_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)G_(k) 1341320 2189 220422004 22019 CTTGATGTAGTGGGAG^(m)C_(ks)T_(ks)T_(ds)G_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)G 20 976_(ds)T_(ds)G_(ks)G_(es)G_(ks)A_(es)G_(k) 1341324 2252 2267 22067 22082AGAGGATAGTCCATGC A_(ks)G_(ks)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)A_(ds)G_(ds)T70 354 _(ds) ^(m)C_(ds) ^(m)C_(ks)A_(es)T_(ks)G_(es) ^(m)C_(k) 1341330N/A N/A  9334  9349 CGATCCTATATACATC ^(m)C_(ks)G_(ks)A_(ds)T_(ds)^(m)C_(ds) ^(m)C_(ds)T_(ds)A_(ds)T_(d) 29 2788 _(s)A_(ds)T_(ds)A_(ks)^(m)C_(es)A_(ks)T_(es) ^(m)C_(k) 1341331 N/A N/A  9516  9531ACACTAATATTGAGGC A_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds) 55 1928T_(ds)T_(ds)G_(ks)A_(es)G_(ks)G_(es) ^(m)C_(k) 1341336 2353 2368 2216822183 ATAACTACAAGAGGTT A_(ks)T_(ks)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds) 46 1133 A_(ds)G_(ds)A_(ks)G_(es)G_(ks)T_(es)T_(k)1341340 N/A N/A 11546 11561 TCTTGACAATGGTTGC T_(ks)^(m)C_(ks)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds)A_(ds) 37 2199T_(ds)G_(ds)G_(ks)T_(es)T_(ks)G_(es) ^(m)C_(k) 1341341 N/A N/A  9968 9983 AGTAGTGTAAGCTGAGA_(ks)G_(ks)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(d) 52 2155_(s)G_(ds) ^(m)C_(ks)T_(es)G_(ks)A_(es)G_(k) 1341349 N/A N/A  9603  9618CACATATGTGAAGAGC ^(m)C_(ks)A_(ks)^(m)C_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 53 760G_(ds)A_(ds)A_(ks)G_(es)A_(ks)G_(es) ^(m)C_(k) 1341352 N/A N/A 1549815513 TGCTGCATTAATGCCA T_(ks)G_(ks) ^(m)C_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds) 30 2485 A_(ds)A_(ds)T_(ks)G_(es) ^(m)C_(ks)^(m)C_(es)A_(k) 1341355 N/A N/A 14918 14933 TAATACATTAGCAAGCT_(ks)A_(ks)A_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds)A 34 2266_(ds)G_(ds) ^(m)C_(ks)A_(es)A_(ks)G_(es) ^(m)C_(k) 1341356 N/A N/A 1241912434 GTAACGGTGATCAAAT G_(ks)T_(ks)A_(ds)A_(ds)^(m)C_(ds)G_(ds)G_(ds)T_(ds)G_(ds) 34 2345 A_(ds)T_(ds)^(m)C_(ks)A_(es)A_(ks)A_(es)T_(k) 1341359 N/A N/A 14199 14214TATTATGTGATTGAGTT_(ks)A_(ks)T_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)A_(ds) 65 73T_(ds)T_(ks)G_(es)A_(ks)G_(es)T_(k) 1341362 N/A N/A 16384 16399AATCCCAACCAAACTT A_(ks)A_(ks)T_(ds) ^(m)C_(ds) ^(m) _(ks)C_(ds)^(m)C_(ds)A_(ds)A_(ds) ^(m) 17 2755 C_(ds) ^(m)C_(ds)A_(ds)A_(ks)A_(es)^(m)C_(ks)T_(es)T_(k) 1341367 N/A N/A 16129 16144 TCCATAATAATAGCTCT_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds) 41 546A_(ds)T_(ds)A_(ks)G_(es) ^(m)C_(ks)T_(es) ^(m)C_(k) 1341369 N/A N/A16223 16238 CTTTTTATAGACTGGG^(m)C_(ks)T_(ks)T_(ds)T_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)G 37 857_(ds)A_(ds) ^(m)C_(ks)T_(es)G_(ks)G_(es)G_(k) 1341372 N/A N/A 1809718112 GAAATTGATACACCAAG_(ks)A_(ks)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds)A_(ds)T_(ds)A_(d) 68 315 _(s)^(m)C_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)A_(k) 1341373 N/A N/A 1799018005 TTAGTATAGTTATCTTT_(ks)T_(ks)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)G_(ds)T_(ds) 33 2366T_(ds)A_(ks)T_(es) ^(m)C_(ks)T_(es)T_(k) 1341383 N/A N/A 18697 18712CAAAAGACTTTGAGAC ^(m)C_(ks)A_(ks)A_(ds)A_(ds)A_(ds)G_(ds)A_(ds)^(m)C_(ds)T_(d) 32 2186 _(s)T_(ds)T_(ds)G_(ks)A_(es)G_(ks)A_(es)^(m)C_(k) 1341386 N/A N/A 19910 19925 CATCTTAAGATACCCA^(m)C_(ks)A_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 59 475A_(ds)T_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks) ^(m)C_(es)A_(k) 1341394 N/A N/A20385 20400 TAGTAATCACAAGTAA T_(ks)A_(ks)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds)A_(ds) ^(m) 55 1489 C_(ds)A_(ds)A_(ks)G_(es)T_(ks)A_(es)A_(k)1341395 N/A N/A 20112 20127 ATCAAGACATTCTAGC A_(ks)T_(ks)^(m)C_(ds)A_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(d) 30 1488_(s)T_(ds)T_(ds) ^(m)C_(ks)T_(es)A_(ks)G_(es) ^(m)C_(k) 1341397 N/A N/A20192 20207 GCAGTTATTAGAAGTC G_(ks)^(m)C_(ks)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds)T_(ds)A 68 398_(ds)G_(ds)A_(ks)A_(es)G_(ks)T_(es) ^(m)C_(k) 1341402 N/A N/A 1279912814 GCTGTAAGAGTCAGTA G_(ks)^(m)C_(ks)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 42 693 G_(ds)T_(ds)^(m)C_(ks)A_(es)G_(ks)T_(es)A_(k) 1341404 N/A N/A 12499 12514AGAAATTCACCTTGAC A_(ks)G_(ks)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) ^(m) 33 2284 C_(ds) ^(m)C_(ds)T_(ks)T_(es)G_(ks)A_(es)^(m)C_(k) 1341408 N/A N/A 20486 20501 AACTTCATAGTGGACT A_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)A_(ds) 68 2555G_(ds)T_(ds)G_(ks)G_(es)A_(ks) ^(m)C_(es)T_(k) 1341416 N/A N/A 1395613971 TACCTCTAAGTTAGCC T_(ks)A_(ks) ^(m)C_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(d) 20 2249 _(s)G_(ds)T_(ds)T_(ks)A_(es)G_(ks)^(m)C_(es) ^(m)C_(k) 1341429 N/A N/A 14192 14207 TGATTGAGTTCTCCACT_(ks)G_(ks)A_(ds)T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)T_(ds)T_(ds) 32 2116^(m)C_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es) ^(m)C_(k) 1341535 1074 108920889 20904 TGCCAAACCAATGTTT T_(ks)G_(ks) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m) 61 2673C_(ds)A_(ds)A_(ds)T_(ks)G_(es)T_(ks)T_(es)T_(k) 1341539 1310 1325 2112521140 CTTAAACCTTCCCTGT ^(m)C_(ks)T_(ks)T_(ds)A_(ds)A_(ds)A_(ds)^(m)C_(ds) ^(m)C_(ds)T_(d) 36 1823 _(s)T_(ds) ^(m)C_(ds) ^(m)C_(ks)^(m)C_(es)T_(ks)G_(es)T_(k) 1341549 1330 1345 21145 21160TGGAATGCTACTTGAA T_(ks)G_(ks)G_(ds)A_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds) 68 2203 A_(ds) ^(m)C_(ds)T_(ks)T_(es)G_(ks)A_(es)A_(k)1341556 1336 1351 21151 21166 ACAGATTGGAATGCTA A_(ks)^(m)C_(ks)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)G_(ds)G_(ds) 49 1668A_(ds)A_(ds)T_(ks)G_(es) ^(m)C_(ks)T_(es)A_(k) 1341570 1707 1722 2152221537 TCTGGGACCAAGGATA T_(ks) ^(m)C_(ks)T_(ds)G_(ds)G_(ds)G_(ds)A_(ds)^(m)C_(ds) ^(m)C 56 1830 _(ds)A_(ds)A_(ds)G_(ks)G_(es)A_(ks)T_(es)A_(k)1341572 1616 1631 21431 21446 GGTCACCTTTCATAAT G_(ks)G_(ks)T_(ds)^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(d) 52 1985 _(s)T_(ds)^(m)C_(ds)A_(ks)T_(es)A_(ks)A_(es)T_(k) 1341579 1771 1786 21586 21601TAGCCAGTACAGTTCC T_(ks)A_(ks)G_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 57 1987^(m)C_(ds)A_(ds)G_(ks)T_(es)T_(ks) ^(m)c_(es) ^(m)C_(k) 1341581 17161731 21531 21546 CTAAACATCTCTGGGA ^(m)C_(ks)T_(ks)A_(ds)A_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds) ^(m)C 29 2259 _(ds)T_(ds)^(m)C_(ds)T_(ks)G_(es)G_(ks)G_(es)A_(k) 1341582 2196 2211 22011 22026GATTAGTCTTGATGTA G_(ks)A_(ks)T_(ds)T_(ds)A_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds)T 56 1521 _(ds)G_(ds)A_(ks)T_(es)G_(ks)T_(es)A_(k)1341584 1776 1791 21591 21606 TGTAATAGCCAGTACAT_(ks)G_(ks)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds) ^(m) 45 352C_(ds)A_(ds)G_(ks)T_(es)A_(ks) ^(m)C_(es)A_(k) 1341592 N/A N/A 1157811593 GTTATTCTCTTGACAA G_(ks)T_(ks)T_(ds)A_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ds) 27 2575 T_(ds)T_(ds)G_(ks)A_(es)^(m)C_(ks)A_(es)A_(k) 1341602 N/A N/A 16292 16307 TTAGTTAGAATAGTCTT_(ks)T_(ks)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)A_(d) 53 1714_(s)T_(ds)A_(ks)G_(es)T_(ks) ^(m)C_(es)T_(k) 1341617 N/A N/A 17995 18010TGAAGTTAGTATAGTTT_(ks)G_(ks)A_(ds)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds)G_(ds)T_(d) 46 1405_(s)A_(ds)T_(ks)A_(es)G_(ks)T_(es)T_(k)

TABLE 42 Inhibition of HSD17B13 RNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: % SEQ Compound 1 Start1 Stop 2 Start 2 Stop Sequence Chemistry Notation in- ID Number SiteSite Site Site (5′ to 3′) (5′ to 3′) hibition NO 1245927 N/A N/A  3433 3448 AGTAGATGGTAAGTCAA_(ks)G_(ks)T_(ks)A_(ds)G_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T_(d) 84 121_(s)A_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1246023 N/A N/A  5046  5061GAGTGAATCATTCAGT G_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds) 83 1526 A_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)T_(k)1340984 1497 1512 21312 21327 AGTTGCACCGTTTTGGA_(ks)G_(ks)T_(ks)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C 43 1905_(ds)G_(ds)T_(ds)T_(ds)T_(ks)T_(ks)G_(ks)G_(e) 1340987 1489 1504 2130421319 CGTTTTGGGCTAATGA^(m)C_(ks)G_(ks)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m) 52 1282C_(ds)T_(ds)A_(ds)A_(ks)T_(ks)G_(ks)A_(e) 1340990 1618 1633 21433 21448TCGGTCACCTTTCATA T_(ks) ^(m)C_(ks)G_(ks)G_(ds)T_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds) ^(m) 72 116 C_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ks)A_(ks)T_(ks)A_(e) 1340997 1622 1637 21437 21452AGAGTCGGTCACCTTT A_(ks)G_(ks)A_(ks)G_(ds)T_(ds)^(m)C_(ds)G_(ds)G_(ds)T_(ds) ^(m) 66 428 C_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ks)T_(ks)T_(ks)T_(e) 1341001 1626 1641 21441 21456AAATAGAGTCGGTCAC A_(ks)A_(ks)A_(ks)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)^(m) 48 740 C_(ds)G_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(e) 13410051630 1645 21445 21460 TTTAAAATAGAGTCGGT_(ks)T_(ks)T_(ks)A_(ds)A_(ds)A_(ds)A_(ds)T_(ds)A_(ds)G_(d) 58 1051_(s)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)G_(ks)G_(e) 1341018 1710 1725 2152521540 ATCTCTGGGACCAAGG A_(ks)T_(ks) ^(m)C_(ks)T_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ds)G_(ds) 53 37 A_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ks)A_(ks)G_(ks)G_(e) 1341019 1714 1729 21529 21544AAACATCTCTGGGACC A_(ks)A_(ks)A_(ks) ^(m)C_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m)C 48 2129 _(ds)T_(ds)G_(ds)G_(ds)G_(ks)A_(ks)^(m)C_(ks) ^(m)C_(e) 1341026 1768 1783 21583 21598 CCAGTACAGTTCCTTT^(m)C_(ks) ^(m)C_(ks)A_(ks)G_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ds)G 76 1753_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks)T_(ks)T_(e) 1341029 17501765 21565 21580 CTGTGTTAGCTTTAAT^(m)C_(ks)T_(ks)G_(ks)T_(ds)G_(ds)T_(ds)T_(ds)A_(ds)G_(ds) ^(m) 50 1286C_(ds)T_(ds)T_(ds)T_(ks)A_(ks)A_(ks)T_(e) 1341031 2193 2208 22008 22023TAGTCTTGATGTAGTG T_(ks)A_(ks)G_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds)T 61 1288_(ds)G_(ds)T_(ds)A_(ks)G_(ks)T_(ks)G_(e) 1341036 1778 1793 21593 21608TATGTAATAGCCAGTAT_(ks)A_(ks)T_(ks)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)G_(d) 82 508 _(s)^(m)C_(ds) ^(m)C_(ds)A_(ks)G_(ks)T_(ks)A_(e) 1341038 1782 1797 2159721612 TTCTTATGTAATAGCC T_(ks)T_(ks)^(m)C_(ks)T_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A 73 819_(ds)A_(ds)T_(ds)A_(ks)G_(ks) ^(m)C_(ks) ^(m)C_(e) 1341047 2247 226222062 22077 ATAGTCCATGCAAAAG A_(ks)T_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)T_(ds) 29 2436 G_(ds)^(m)C_(ds)A_(ds)A_(ks)A_(ks)A_(ks)G_(e) 1341058 N/A N/A  9330  9345CCTATATACATCCAAG ^(m)C_(ks)^(m)C_(ks)T_(ks)A_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(d) 63 1771_(s)A_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)A_(ks)G_(e) 1341063 10821097 20897 20912 GCTGCTAGTGCCAAAC G_(ks) ^(m)C_(ks)T_(ks)G_(ds)^(m)C_(ds)T_(ds)A_(ds)G_(ds)T_(ds) 62 1587 G_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ks)A_(ks)A_(ks) ^(m)C_(e) 1341064 N/A N/A 11855 11870TAAGCAGAATTGTGAA T_(ks)A_(ks)A_(ks)G_(ds)^(m)C_(ds)A_(ds)G_(ds)A_(ds)A_(ds) 52 2361T_(ds)T_(ds)G_(ds)T_(ks)G_(ks)A_(ks)A_(e) 1341067 N/A N/A 11571 11586TCTTGACAATGGTTGA T_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ds)A_(ds)^(m)C_(ds)A_(ds)A_(ds) 61 2440 T_(ds)G_(ds)G_(ds)T_(ks)T_(ks)G_(ks)A_(e)1341069 N/A N/A  9964  9979 GTGTAAGCTGAGAGTTG_(ks)T_(ks)G_(ks)T_(ds)A_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ds) 45 2760G_(ds)A_(ds)G_(ds)A_(ks)G_(ks)T_(ks)T_(e) 1341070 N/A N/A 14199 14214TATTATGTGATTGAGTT_(ks)A_(ks)T_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds)A_(ds) 51 73T_(ds)T_(ds)G_(ks)A_(ks)G_(ks)T_(e) 1341073 N/A N/A 15498 15513TGCTGCATTAATGCCA T_(ks)G_(ks) ^(m)C_(ks)T_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds) 6 2485 A_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(ks)A_(e) 1341079 N/A N/A 14918 14933 TAATACATTAGCAAGCT_(ks)A_(ks)A_(ks)T_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds)A 35 2266_(ds)G_(ds) ^(m)C_(ds)A_(ks)A_(ks)G_(ks) ^(m)C_(e) 1341082 N/A N/A 1638016395 CCAACCAAACTTCCAG ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds) 47 2539 A_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ks)^(m)C_(ks)A_(ks)G_(e) 1341083 1078 1093 20893 20908 CTAGTGCCAAACCAAT^(m)C_(ks)T_(ks)A_(ks)G_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)A 61 1276_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)A_(ks)T_(e) 1341085 N/A N/A16287 16302 TAGAATAGTCTTCAGCT_(ks)A_(ks)G_(ks)A_(ds)A_(ds)T_(ds)A_(ds)G_(ds)T_(ds) ^(m) 50 1403C_(ds)T_(ds)T_(ds) ^(m)C_(ks)A_(ks)G_(ks) ^(m)C_(e) 1341090 N/A N/A18697 18712 CAAAAGACTTTGAGAC^(m)C_(ks)A_(ks)A_(ks)A_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(d) 13 2186_(s)T_(ds)T_(ds)G_(ds)A_(ks)G_(ks)A_(ks) ^(m)C_(e) 1341095 N/A N/A 1809918114 CTGAAATTGATACACC^(m)C_(ks)T_(ks)G_(ks)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds) 75 393A_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(ks) ^(m)C_(ks) ^(m)C_(e) 1341098 N/A N/A17992 18007 AGTTAGTATAGTTATCA_(ks)G_(ks)T_(ks)T_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(d) 47 1249_(s)G_(ds)T_(ds)T_(ks)A_(ks)T_(ks) ^(m)C_(e) 1341107 N/A N/A 19907 19922CTTAAGATACCCAGGT^(m)C_(ks)T_(ks)T_(ks)A_(ds)A_(ds)G_(ds)A_(ds)T_(ds)Aci_(s) ^(m) 45 241C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)G_(ks)G_(ks)T_(e) 1341108 N/A N/A19911 19926 GCATCTTAAGATACCC G_(ks) ^(m)C_(ks)A_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds) 84 553 G_(ds)A_(ds)T_(ds)A_(ks)^(m)C_(ks) ^(m)C_(ks) ^(m)C_(e) 1341110 N/A N/A 20383 20398GTAATCACAAGTAAGG G_(ks)T_(ks)A_(ks)A_(ds)T_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)A_(ds) 56 1411 A_(ds)G_(ds)T_(ds)A_(ks)A_(ks)G_(ks)G_(e)1341116 N/A N/A 20194 20209 TTGCAGTTATTAGAAG T_(ks)T_(ks)G_(ks)^(m)C_(ds)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T 10 2123_(ds)T_(ds)A_(ds)G_(ks)A_(ks)A_(ks)G_(e) 1341122 1086 1101 20901 20916GACTGCTGCTAGTGCC G_(ks)A_(ks) ^(m)C_(ks)T_(ds)G_(ds)^(m)C_(ds)T_(ds)G_(ds) ^(m)C 49 1899 _(ds)T_(ds)A_(ds)G_(ds)T_(ks)G_(ks)^(m)C_(ks) ^(m)C_(e) 1341123 N/A N/A 12801 12816 AGGCTGTAAGAGTCAGA_(ks)G_(ks)G_(ks) ^(m)C_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 49 2809G_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(ks)G_(e) 1341125 N/A N/A 1250312518 TTGCAGAAATTCACCT T_(ks)T_(ks)G_(ks)^(m)C_(ds)A_(ds)G_(ds)A_(ds)A_(ds)A_(ds) 29 2528 T_(ds)T_(ds)^(m)C_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(ks)T_(e) 1341134 N/A N/A 13954 13969CCTCTAAGTTAGCCCC ^(m)C_(ks) ^(m)C_(ks)T_(ks)^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(d) 16 1084 _(s)T_(ds)A_(ds)G_(ds)^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(e) 1341136 N/A N/A 14168 14183ATAGCAAGCCAACAGA A_(ks)T_(ks)A_(ks)G_(ds) ^(m)C_(ds)A_(ds)A_(ds)G_(ds)^(m)C_(d) 30 2633 _(s) ^(m)C_(ds)A_(ds)A_(ds)^(m)C_(ks)A_(ks)G_(ks)A_(e) 1341144 1258 1273 21073 21088TAGCTTTTGTCCACCT T_(ks)A_(ks)G_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds)T 65 1900 _(ds) ^(m)C_(ds)^(m)C_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(ks)T_(e) 1341146 1200 1215 2101521030 ATGTTTATGTAAGCACA_(ks)T_(ks)G_(ks)T_(ds)T_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) 73 2622A_(ds)A_(ds)G_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(e) 1341148 N/A N/A 1419214207 TGATTGAGTTCTCCACT_(ks)G_(ks)A_(ks)T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)T_(ds)T_(ds) 30 2116^(m)C_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(e) 1341149  606  62110492 10507 AATATGGGATGAGGTAA_(ks)A_(ks)T_(ks)A_(ds)T_(ds)G_(ds)G_(ds)G_(ds)A_(ds)T_(d) 47 1424_(s)G_(ds)A_(ds)G_(ks)G_(ks)T_(ks)A_(e) 1341155 1312 1327 21127 21142GTCTTAAACCTTCCCT G_(ks)T_(ks) ^(m)C_(ks)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds)^(m)C_(ds) 50 1901 ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks)^(m)C_(ks)T_(e) 1341157 1316 1331 21131 21146 AACAGTCTTAAACCTTA_(ks)A_(ks) ^(m)C_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds) 57 188A_(ds)A_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(ks)T_(e) 1341161 1322 133721137 21152 TACTTGAACAGTCTTA T_(ks)A_(ks)^(m)C_(ks)T_(ds)T_(ds)G_(ds)A_(ds)A_(ds) ^(m)C_(ds) 65 656A_(ds)G_(ds)T_(ds) ^(m)C_(ks)T_(ks)T_(ks)A_(e) 1341162 1333 1348 2114821163 GATTGGAATGCTACTTG_(ks)A_(ks)T_(ks)T_(ds)G_(ds)G_(ds)A_(ds)A_(ks)T_(ds)G_(d) 59 1435 _(s)^(m)C_(ds)T_(ds)A_(ks) ^(m)C_(ks)T_(ks)T_(e) 1341169 1326 1341 2114121156 ATGCTACTTGAACAGT A_(ks)T_(ks)G_(ks) ^(m)C_(ds)T_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds) 50 967 G_(ds)A_(ds)A_(ds)^(m)C_(ks)A_(ks)G_(ks)T_(e) 1341220 1342 1357 21157 21172ATGGCTACAGATTGGA A_(ks)T_(ks)G_(ks)G_(ds) ^(m)C_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds) 65 111 G_(ds)A_(ds)T_(ds)T_(ks)G_(ks)G_(ks)A_(e)1341283 1356 1371 21171 21186 TGATATTCTGTGGCATT_(ks)G_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G 74 1124_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(ks)T_(e) 1341309 1352 1367 2116721182 ATTCTGTGGCATGGCT A_(ks)T_(ks)^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds) ^(m) 68 2328C_(ds)A_(ds)T_(ds)G_(ks)G_(ks) ^(m)C_(ks)T_(e) 1341366 1364 1379 2117921194 GTTCTTGTTGATATTC G_(ks)T_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)G_(ds)T_(ds)T_(ds)G 69 1436_(ds)A_(ds)T_(ds)A_(ks)T_(ks)T_(ks) ^(m)C_(e) 1341420 1418 1433 2123321248 TTGAGATAAAGCTGCCT_(ks)T_(ks)G_(ks)A_(ds)G_(ds)A_(ds)T_(ds)A_(ds)A_(ks)A_(d) 43 1670_(s)G_(ds) ^(m)C_(ds)T_(ks)G_(ks) ^(m)C_(ks) ^(m)C_(e) 1341422 1389 140421204 21219 TCTCTTAGCTGTGCAC T_(ks) ^(m)C_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(d) 69 346_(s)T_(ds)G_(ds)T_(ds)G_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(e) 1341423 14221437 21237 21252 CAGGTTGAGATAAAGC^(m)C_(ks)A_(ks)G_(ks)G_(ds)T_(ds)T_(ds)G_(ds)A_(ds)G_(ds) 63 1982A_(ds)T_(ds)A_(ds)A_(ks)A_(ks)G_(ks) ^(m)C_(e) 1341430 1493 1508 2130821323 GCACCGTTTTGGGCTA G_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(ds)^(m)C_(ds)G_(ds)T_(ds)T_(ds)T_(d) 45 1593 _(s)T_(ds)G_(ds)G_(ds)G_(ks)^(m)C_(ks)T_(ks)A_(e) 1341438 1504 1519 21319 21334 AGAATAGAGTTGCACCA_(ks)G_(ks)A_(ks)A_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T 58 426_(ds)T_(ds)G_(ds) ^(m)C_(ks)A_(ks) ^(m)C_(ks) ^(m)C_(e) 1341440 14611476 21276 21291 CTAGGGAAATCTTTCA^(m)C_(ks)T_(ks)A_(ks)G_(ds)G_(ds)G_(ds)A_(ds)A_(ds)A_(ds) 55 659 T_(ds)^(m)C_(ds)T_(ds)T_(ks)T_(ks) ^(m)C_(ks)A_(e) 1341443 1614 1629 2142921444 TCACCTTTCATAATGT T_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) ^(m) 41 2109C_(ds)A_(ds)T_(ds)A_(ds)A_(ks)T_(ks)G_(ks)T_(e) 1341444  805  820 1568615701 GTAAGTATTCCATCTAG_(ks)T_(ks)A_(ks)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)T_(ds) ^(m)C 39 1038_(ds) ^(m)C_(ds)A_(ds)T_(ks) ^(m)C_(ks)T_(ks)A_(e) 1341445  613  628 N/AN/A CTGGAACAATATGGGA ^(m)C_(ks)T_(ks)G_(ks)G_(ds)A_(ds)A_(ds)^(m)C_(ds)A_(ds)A_(d) 36 1969_(s)T_(ds)A_(ds)T_(ds)G_(ks)G_(ks)G_(ks)A_(e) 1341452 1718 1733 2153321548 GTCTAAACATCTCTGG G_(ks)T_(ks) ^(m)C_(ks)T_(ds)A_(ds)A_(ds)A_(ds)^(m)C_(ds)A_(ds) 49 429 G_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(ks)G_(ks)T_(e)1341453 1774 1789 21589 21604 TAATAGCCAGTACAGTT_(ks)A_(ks)A_(ks)T_(ds)A_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) 64 196G_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(ks)G_(ks)T_(e) 1341459 1074 1089 2088920904 TGCCAAACCAATGTTT T_(ks)G_(ks) ^(m)C_(ks)^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m) 43 2673C_(ds)A_(ds)A_(ds)T_(ds)G_(ks)T_(ks)T_(ks)T_(e) 1341461 N/A N/A  9511 9526 AATATTGAGGCACTGGA_(ks)A_(ks)T_(ks)A_(ds)T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)G_(d) 36 1538 _(s)^(m)C_(ds)A_(ds) ^(m)C_(ks)T_(ks)G_(ks)G_(e) 1341462 N/A N/A  9598  9613ATGTGAAGAGCTGGTA A_(ks)T_(ks)G_(ks)T_(ds)G_(ds)A_(ks)A_(ds)G_(ds)A_(ds)G56 527 _(ds) ^(m)C_(ds)T_(ds)G_(ks)G_(ks)T_(ks)A_(e) 1341464 2257 227222072 22087 AAACAAGAGGATAGTC A_(ks)A_(ks)A_(ks)^(m)C_(ds)A_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 45 744G_(ds)A_(ks)T_(ds)A_(ks)G_(ks)T_(ks) ^(m)C_(e) 1341465 2186 2201 2200122016 GATGTAGTGGGAGTCGG_(ks)A_(ks)T_(ks)G_(ds)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds)G_(d) 42 743_(s)G_(ds)A_(ds)G_(ks)T_(ks) ^(m)C_(ks)G_(e) 1341470 N/A N/A 12416 12431ACGGTGATCAAATGTA A_(ks) ^(m)C_(ks)G_(ks)G_(ds)T_(ds)G_(ds)A_(ds)T_(ds)^(m)C_(ds) 41 2205 A_(ds)A_(ds)A_(ds)T_(ks)G_(ks)T_(ks)A_(e) 1341472 N/AN/A 12426 12441 CAGGGTGGTAACGGTG^(m)C_(ks)A_(ks)G_(ks)G_(ds)G_(ds)T_(ds)G_(ds)G_(ds)T_(ds) 39 2729A_(ds)A_(ds) ^(m)C_(ds)G_(ks)G_(ks)T_(ks)G_(e) 1341478 N/A N/A 1799718012 TATGAAGTTAGTATAGT_(ks)A_(ks)T_(ks)G_(ds)A_(ds)A_(ds)G_(ds)T_(ds)T_(ds)A_(d) 13 1560_(s)G_(ds)T_(ds)A_(ks)T_(ks)A_(ks)G_(e) 1341480 N/A N/A 16134 16149GATGCTCCATAATAAT G_(ks)A_(ks)T_(ks)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)^(m)C_(ds)A 15 2049 _(ds)T_(ds)A_(ds)A_(ds)T_(ks)A_(ks)A_(ks)T_(e)1341486 N/A N/A 16124 16139 AATAATAGCTCTATTGA_(ks)A_(ks)T_(ks)A_(ds)A_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds) 3 2410T_(ds) ^(m)C_(ds)T_(ds)A_(ks)T_(ks)T_(ks)G_(e) 1341494 N/A N/A 1991519930 GAGTGCATCTTAAGAT G_(ks)A_(ks)G_(ks)T_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds) 34 2256T_(ds)T_(ds)A_(ds)A_(ks)G_(ks)A_(ks)T_(e) 1341496 N/A N/A 17987 18002GTATAGTTATCTTCTCG_(ks)T_(ks)A_(ks)T_(ds)A_(ds)G_(ds)T_(ds)T_(ds)A_(ks)T_(ds) 68 937^(m)C_(ds)T_(ds)T_(ks) ^(m)C_(ks)T_(ks) ^(m)C_(e) 1341499 N/A N/A 2048920504 CATAACTTCATAGTGG ^(m)C_(ks)A_(ks)T_(ks)A_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(d) 16 866_(s)A_(ds)T_(ds)A_(ds)G_(ks)T_(ks)G_(ks)G_(e) 1341501 N/A N/A 2010920124 AAGACATTCTAGCCTG A_(ks)A_(ks)G_(ks)A_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) 40 2744 T_(ds)A_(ds)G_(ds)^(m)C_(ks) ^(m)C_(ks)T_(ks)G_(e) 1341506 N/A N/A 20119 20134TTACAGCATCAAGACA T_(ksks)A_(ks) ^(m)C_(ds)A_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ds) 44 2409 ^(m)C_(ds)A_(ds)A_(ds)G_(ks)A_(ks)^(m)C_(ks)A_(e) 1341517 N/A N/A 20479 20494 TAGTGGACTTCATTAGT_(ks)A_(ks)G_(ks)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds)T 22 2351_(ds) ^(m)C_(ds)A_(ds)T_(ks)T_(ks)A_(ks)G_(e)

TABLE 43 Inhibition of HSD17B13 RNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: % SEQ Compound 1 Start1 Stop 2 Start 2 Stop Sequence Chemistry Notation in- ID Number SiteSite Site Site (5′ to 3′) (5′ to 3′) hibition NO 1245927 N/A N/A 34333448 AGTAGATGGTAAGTCA A_(ks)G_(ks)T_(ks)A_(ds)G_(ds)A_(ds)T_(ds)G_(ds)G88 121 _(ds)T_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1246023 N/A N/A5046 5061 GAGTGAATCATTCAGTG_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds)A_(ksds)T_(ds) ^(m) 84 1526C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)T_(k) 1340982 1490 150521305 21320 CCGTTTTGGGCTAATG ^(m)C_(ks)^(m)C_(ks)G_(ks)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds) 69 1360 G_(ds)G_(ds)^(m)C_(ds)T_(ds)A_(ks)A_(ks)T_(ks)G_(e) 1340988 1494 1509 21309 21324TGCACCGTTTTGGGCT T_(ks)G_(ks) ^(m)C_(k)A_(ds) ^(m)C_(ds)^(m)C_(ds)G_(ds)T 43 1671 _(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ks)G_(ks)^(m)C_(ks)T_(e) 1340993 1619 1634 21434 21449 GTCGGTCACCTTTCATG_(ks)T_(ks) ^(m)C_(ks)G_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(d) 68 194 _(s)^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ks) ^(m)C_(ks)A_(ks)T_(e) 13409941598 1613 21413 21428 ATCTTATAAGACTATA A_(ks)T_(ks)^(m)C_(ks)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 53 2661 A_(ds)G_(ds)A_(ds)^(m)C_(ds)T_(ks)A_(ks)T_(ks)A_(e) 1341006 1627 1642 21442 21457AAAATAGAGTCGGTCA A_(ks)A_(ks)A_(ks)A_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G 65817 _(ds)T_(ds) ^(m)C_(ds)G_(Ds)G_(ks)T_(ks) ^(m)C_(ks)A_(e) 1341008 808  823 15689 15704 TTGGTAAGTATTCCATT_(ks)T_(ks)G_(ks)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(d) 28 2750_(s)A_(ds)T_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(ks)T_(e) 1341009 16231638 21438 21453 TAGAGTCGGTCACCTT T_(ks)A_(ks)Cr_(ks)A_(ds)G_(ds)T_(ds)^(m)C_(ds)G_(ds) 59 506 G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ks)^(m)C_(ks)T_(ks)T_(e) 1341012 1719 1734 21534 21549 TGTCTAAACATCTCTGT_(ks)G_(ks)T_(ks) ^(m)C_(ds)T_(ds)A_(ds)A_(ds)A_(ds) ^(m) 69 507C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks)T_(ks)G_(e) 1341014 17111726 21526 21541 CATCTCTGGGACCAAG ^(m)C_(ks)A_(ks)T_(ks)^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)G 42 117 _(ds)G_(ds)G_(ds)A_(ds)^(m)C_(ds) ^(m)C_(ks)A_(ks)A_(ks)G_(e) 1341016 1715 1730 21530 21545TAAACATCTCTGGGAC T_(ks)A_(ks)A_(ks)A_(ds) ^(m)C_(ds)A_(ds)T_(ds)^(m)C_(d) 32 351 _(s)T_(ds) ^(m)C_(ds)T_(ds)G_(ds)G_(ks)G_(ks)A_(ks)^(m)C_(e) 1341020 1017 1032 20832 20847 CAGCATTGATTCGAAA^(m)C_(ks)A_(ks)G_(ks) ^(m)C_(ds)A_(ds)T_(ds)T_(ds)G_(d) 53 263_(s)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)G_(ks)A_(ks)A_(ks)A_(e) 1341025 17751790 21590 21605 GTAATAGCCAGTACAGG_(ks)T_(ks)A_(ks)A_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds) 62 274^(m)C_(ds)A_(ds)G_(ds)T_(ds)A_(ks) ^(m)C_(ks)A_(ks)G_(e) 1341027 17511766 21566 21581 CCTGTGTTAGCTTTAA ^(m)C_(ks)^(m)C_(ks)T_(ks)G_(ds)T_(ds)G_(ds)T_(ds)T_(ds) 66 1364 A_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ks)T_(ks)A_(ks)A_(e) 1341028 1770 1785 21585 21600AGCCAGTACAGTTCCT A_(ks)G_(ks) ^(m)C_(ks)^(m)C_(ds)A_(ds)G_(ds)T_(ds)A_(d) 59 1909 _(s)^(m)C_(ds)A_(ds)G_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(ks)T_(e) 13410321779 1794 21594 21609 TTATGTAATAGCCAGTT_(ks)T_(ks)A_(ks)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T_(d) 77 586_(s)A_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)G_(ks)T_(e) 1341035 21872202 22002 22017 TGATGTAGTGGGAGTCT_(ks)G_(ks)A_(ks)T_(ds)G_(ds)T_(ds)A_(ds)G_(ds)T_(d) 77 820_(s)G_(ds)G_(ds)G_(ds)A_(ks)G_(ks)T_(ks) ^(m)C_(e) 1341037 1783 179821598 21613 TTTCTTATGTAATAGC T_(ks)T_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)G 60 2128_(ds)T_(ds)A_(ds)A_(ds)T_(ks)A_(ks)G_(ks) ^(m)C_(e) 1341041 1079 109420894 20909 GCTAGTGCCAAACCAA G_(ks)^(m)C_(ks)T_(ks)A_(ds)G_(ds)T_(ds)G_(ds) ^(m)C_(d) 70 1354 _(s)^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(e) 13410462250 2265 22065 22080 AGGATAGTCCATGCAAA_(ks)G_(ks)G_(ks)A_(ds)T_(ds)A_(ds)G_(ds)T_(ds) ^(m) 61 2690 C_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)A_(ks)A_(e) 1341050 N/A N/A 93329347 ATCCTATATACATCCA A_(ks)T_(ks) ^(m)C_(ks)^(m)C_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 75 1927 T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 1341052 N/A N/A 99669981 TAGTGTAAGCTGAGAG T_(ks)A_(ks)G_(ks)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G82 1852 _(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ks)G_(ksSks)G_(e) 1341054 N/A N/A9601 9616 CATATGTGAAGAGCTG^(m)C_(ks)A_(ks)T_(ks)A_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 50 683A_(ds)A_(ds)G_(ds)A_(ds)G_(ks) ^(m)C_(ks)T_(ks)G_(e) 1341055 N/A N/A9514 9529 ACTAATATTGAGGCAC A_(ks)^(m)C_(ks)T_(ks)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 62 1772T_(ds)G_(ds)A_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(e) 1341061 N/AN/A 12419 12434 GTAACGGTGATCAAAT G_(ks)T_(ks)A_(ks)A_(ds)^(m)C_(ds)G_(ds)G_(ds)T_(ds) 32 2345 G_(ds)A_(ds)T_(ds)^(m)C_(ds)A_(ks)A_(ks)A_(ks)T_(e) 1341062 N/A N/A 11548 11563TCTCTTGACAATGGTT T_(ks) ^(m)C_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) 84 1389 11573 11588^(m)C_(ds)A_(ds)A_(ds)T_(ds)G_(ks)G_(ks)T_(ks)T_(e) 100 1341080 N/A N/A16289 16304 GTTAGAATAGTCTTCAG_(ks)T_(ks)T_(ks)A_(ds)G_(ds)A_(ds)A_(ds)T_(ds)A 71 1481_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ks)T_(ks) ^(m)C_(ks)A_(e) 1341087 N/A N/A16382 16397 TCCCAACCAAACTTCC T_(ks) ^(m)C_(ks) ^(m)C_(ks)^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds) 24 2026 ^(m)C_(ds)A_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ks)T_(ks) ^(m)C_(ks) ^(m)C_(e) 1341088 N/A N/A 16127 16142CATAATAATAGCTCTA ^(m)C_(ks)A_(ks)T_(ks)A_(ds)A_(ds)T_(ds)A_(ds)A_(ds) 552511 T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks)T_(ks)A_(e) 13410931083 1098 20898 20913 TGCTGCTAGTGCCAAA T_(ks)G_(ks)^(m)C_(ks)T_(ds)G_(ds) ^(m)C_(ds)T_(ds)A_(ds) 56 1665 G_(ds)T_(ds)G_(ds)^(m)C_(ds) ^(m)C_(ks)A_(ks)A_(ks)A_(e) 1341097 N/A N/A 17989 18004TAGTATAGTTATCTTC T_(ks)A_(ks)G_(ks)T_(ds)A_(ds)T_(ds)A_(ds)G_(ds)T_(d)28 1093 _(s)T_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(ks)T_(ks) ^(m)C_(e) 1341099N/A N/A 17994 18009 GAAGTTAGTATAGTTAG_(ks)A_(ks)A_(ks)G_(ds)T_(ds)T_(ds)A_(ds)G_(ds)T 75 1327_(ds)A_(ds)T_(ds)A_(ds)G_(ks)T_(ks)T_(ks)A_(e) 1341100 N/A N/A 1990819923 TCTTAAGATACCCAGG T_(ks)^(m)C_(ks)T_(ks)T_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 48 319 T_(ds)A_(ds)^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)G_(ks)G_(e) 1341105 N/A N/A 1991219927 TGCATCTTAAGATACC T_(ks)G_(ks) ^(m)C_(ks)A_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds) 37 2050 A_(ds)A_(ds)G_(ds)A_(ds)T_(ks)A_(ks)^(m)C_(ks) ^(m)C_(e) 1341113 N/A N/A 20385 20400 TAGTAATCACAAGTAAT_(ks)A_(ks)G_(ks)T_(ds)A_(ds)A_(ds)T_(ds) ^(m)C_(ds) 65 1489 A_(ds)^(m)C_(ds)A_(ds)A_(ds)G_(ks)T_(ks)A_(ks)A_(e) 1341114 N/A N/A 2011220127 ATCAAGACATTCTAGC AT_(ks) ^(m)C_(ks)A_(ds)A_(ds)G_(ds)A_(ds)^(m)C_(d) 52 1488 _(s)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ks)A_(ks)G_(ks)^(m)C_(e) 1341119 1088 1103 20903 20918 TTGACTGCTGCTAGTGT_(ks)T_(ks)G_(ks)A_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds) 50 28T_(ds)G_(ds) ^(m)C_(ds)T_(ds)A_(ks)G_(ks)T_(ks)G_(e) 1341127 N/A N/A20482 20497 TCATAGTGGACTTCAT T_(ks)^(m)C_(ks)A_(ks)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 54 633 G_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ks) ^(m)C_(ks)A_(ks)T_(e) 1341130 N/A N/A 13956 13971TACCTCTAAGTTAGCC T_(ks)A_(ks) ^(m)C_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)A 30 2249 _(ds)A_(ds)G_(ds)T_(ds)T_(ds)A_(ks)G_(ks)^(m)C_(ks) ^(m)C_(e) 1341132 N/A N/A 14194 14209 TGTGATTGAGTTCTCCT_(ks)G_(ks)T_(ks)G_(ds)A_(ds)T_(ds)T_(ds)G_(ds)A_(d) 52 2020_(s)G_(ds)T_(ds)T_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(ks) ^(m)C_(e) 1341133 N/AN/A 14170 14185 GAATAGCAAGCCAACA G_(ks)A_(ks)A_(ks)T_(ds)A_(ds)G_(ds)^(m)C_(ds)A_(ds) 30 1708 A_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)A_(ks)^(m)C_(ks)A_(e) 1341141 1259 1274 21074 21089 GTAGCTTTTGTCCACCG_(ks)T_(ks)A_(ks)G_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)T 67 1978_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks) ^(m)C_(ks) ^(m)C_(e)1341147 1202 1217 21017 21032 GTATGTTTATGTAAGCG_(ks)T_(ks)A_(ks)T_(ds)G_(ds)T_(ds)T_(ds)T_(ds)A_(d) 71 1511_(s)T_(ds)G_(ds)T_(ds)A_(ks)A_(ks)G_(ks) ^(m)C_(e) 1341152 1317 133221132 21147 GAACAGTCTTAAACCT G_(ks)A_(ks)A_(ks)^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(d) 64 266_(s)T_(ds)T_(ds)A_(ds)A_(ds)A_(ks)A_(ks) ^(m)C_(ks) ^(m)C_(ks)T_(e)1341159 1313 1328 21128 21143 AGTCTTAAACCTTCCC A_(ks)G_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds) 61 1979 A_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(e) 1341163 1327 134221142 21157 AATGCTACTTGAACAG A_(ks)A_(ks)T_(ks)G_(ds)^(m)C_(ds)T_(ds)A_(ds) ^(m)C_(d) 50 1045_(s)T_(ds)T_(ds)G_(ds)A_(ds)A_(ks) ^(m)C_(ks)A_(ks)G_(e) 1341168 13231338 21138 21153 CTACTTGAACAGTCTT ^(m)C_(ks)T_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) 71 734 A_(ds)^(m)C_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)T_(ks)T_(e) 1341205 1335 135021150 21165 CAGATTGGAATGCTAC^(m)C_(ks)A_(ks)G_(ks)A_(ds)T_(ds)T_(ds)G_(ds)G_(ds) 61 1590A_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ks)T_(ks)A_(ks) ^(m)C_(e) 1341216 13441359 21159 21174 GCATGGCTACAGATTG G_(ks)^(m)C_(ks)A_(ks)T_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(d) 67 267 _(s)A_(ds)^(m)C_(ds)A_(ds)G_(ds)A_(ks)T_(ks)T_(ks)G_(e) 1341223  696  711 1211412129 GACATGAGGTTTTGAT G_(ks)A_(ks)^(m)C_(ks)A_(ds)T_(ds)G_(ds)A_(ds)G_(ds) 55 647G_(ds)T_(ds)T_(ds)T_(ds)TIc_(s)G_(ks)A_(ks)T_(e) 1341244 1353 1368 2116821183 TATTCTGTGGCATGGC T_(ks)A_(ks)T_(ks)T_(ds)^(m)C_(ds)T_(ds)G_(ds)T_(ds)G 74 890 _(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ks)G_(ks)G_(ks) ^(m)C_(e)  1341335 1357 1372 2117221187 TTGATATTCTGTGGCA T_(ks)T_(ks)G_(ks)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)^(m)C 76 1202 _(ds)T_(ds)G_(ds)T_(ds)G_(ks)G_(ks) ^(m)C_(ks)A_(e)1341353 1366 1381 21181 21196 GTGTTCTTGTTGATATG_(ks)T_(ks)G_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G 66 1514_(ds)T_(ds)T_(ds)G_(ds)A_(ks)T_(ks)A_(ks)T_(e) 1341413 1391 1406 2120621221 GATCTCTTAGCTGTGC G_(ks)A_(ks)T_(ks) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds) 70 502 A_(ds)G_(ds)^(m)C_(ds)T_(ds)G_(ks)T_(ks)G_(ks) ^(m)C_(e) 1341424  794  809 1567515690 ATCTATCAGACTTCTT A_(ks)T_(ks) ^(m)C_(ks)T_(ds)A_(ds)T_(ds)^(m)C_(ds)A_(ds) 51 2728 G_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ks)^(m)C_(ks)T_(ks)T_(e) 1341425 1423 1438 21238 21253 CCAGGTTGAGATAAAG^(m)C_(ks) ^(m)C_(ks)A_(ks)G_(ds)G_(ds)T_(ds)T_(ds)G_(d) 51 33_(s)A_(ds)G_(ds)A_(ds)T_(ds)A_(ks)A_(ks)A_(ks)G_(e) 1341433 1464 147921279 21294 AGGCTAGGGAAATCTT A_(ks)G_(ks)G_(ks)^(m)C_(ds)T_(ds)A_(ds)G_(ds)G_(ds) 55 892 G_(ds)A_(ds)A_(ds)A_(ds)T_(ks)^(m)C_(ks)T_(ks)T_(e) 1341434 1419 1434 21234 21249 GTTGAGATAAAGCTGCG_(ks)T_(ks)T_(ks)G_(ds)A_(ds)G_(ds)Aci_(s)T_(ds)A 59 1748_(ds)A_(ds)A_(ds)G_(ds) ^(m)C_(ks)T_(ks)G_(ks) ^(m)C_(e) 1341439 16151630 21430 21445 GTCACCTTTCATAATG G_(ks)T_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds) ^(m)C_(ds)T_(ds)T 21 1907 _(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ds)A_(ks)A_(ks)T_(ks)G_(e) 1341442 1498 1513 2131321328 GAGTTGCACCGTTTTG G_(ks)A_(ks)G_(ks)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds) 62 1983 ^(m)C_(ds)^(m)C_(ds)G_(ds)T_(ds)T_(ks)T_(ks)T_(ks)G_(e) 1341448 1705 1720 2152021535 TGGGACCAAGGATATA T_(ks)G_(ks)G_(ks)G_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds)A_(d) 55 1674_(s)A_(ds)G_(ds)G_(ds)A_(ds)T_(ks)A_(ks)T_(ks)A_(e) 1341458 2194 220922009 22024 TTAGTCTTGATGTAGT T_(ks)T_(ks)A_(ks)G_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)G 61 1366_(ds)A_(ds)T_(ds)G_(ds)T_(ks)A_(ks)G_(ks)T_(e) 1341463 2350 2365 2216522180 ACTACAAGAGGTTATT A_(ks) ^(m)C_(ks)T_(ks)A_(ds)^(m)C_(ds)A_(ds)A_(ds)G_(d) 58 899_(s)A_(ds)G_(ds)G_(ds)T_(ds)T_(ks)A_(ks)T_(ks)T_(e) 1341468 N/A N/A14204 14219 CAGATTATTATGTGAT^(m)C_(ks)A_(ks)G_(ks)A_(ds)T_(ds)T_(ds)A_(ds)T_(ds) 38 2723T_(ds)A_(ds)T_(ds)G_(ds)T_(ks)G_(ks)A_(ks)T_(e) 1341471 1075 1090 2089020905 GTGCCAAACCAATGTT G_(ks)T_(ks)G_(ks) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds)A_(d) 56 1042 _(s) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ks)G_(ks)T_(ks)T_(e) 1341473 N/A N/A 1185811873 GATTAAGCAGAATTGT G_(ks)A_(ks)T_(ks)T_(ds)A_(ds)A_(ds)G_(ds)^(m)C_(ds) 28 1156 A_(ds)G_(ds)A_(ds)A_(ds)T_(ks)T_(ks)G_(ks)T_(e)1341475 N/A N/A 11543 11558 TGACAATGGTTGCCAC T_(ks)G_(ks)A_(ks)^(m)C_(ds)A_(ds)A_(ds)T_(ds)G_(ds) 45 1233 G_(ds)T_(ds)T_(ds)G_(ds)^(m)C_(ks) ^(m)C_(ks)A_(ks) ^(m)C_(e) 1341485 N/A N/A 16218 16233TATAGACTGGGTAGGA T_(ks)A_(ks)T_(ks)A_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds)55 2808 G_(ds)G_(ds)G_(ds)T_(ds)A_(ks)G_(ks)G_(ks)A_(e) 1341487 N/A N/A15491 15506 TTAATGCCACCCTACC T_(ks)T_(ks)A_(ks)A_(ds)T_(ds)G_(ds)^(m)C_(ds) ^(m)C_(ds) 20 2304 A_(ds) ^(m)C_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ks)A_(ks) ^(m)C_(ks) ^(m)C_(e) 1341489 N/A N/A 18092 18107TGATACACCAATGCAG T_(ks)G_(ks)A_(ks)T_(ds)A_(ds) ^(m)C_(ds)A_(ds)^(m)C_(d) 58 2370 _(s) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)G_(ks)^(m)C_(ks)A_(ks)G_(e) 1341490 N/A N/A 19916 19931 GGAGTGCATCTTAAGAG_(ks)G_(ks)A_(ks)G_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) 40 2810 T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ks)A_(ks)G_(ks)A_(e) 1341491 N/A N/A 1990419919 AAGATACCCAGGTTGC A_(ks)A_(ks)G_(ks)A_(ds)T_(ds)A_(ds) ^(m)C_(ds)^(m)C_(d) 69 2712 _(s) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)T_(ks)T_(ks)G_(ks)^(m)C_(e) 1341497 N/A N/A 18690 18705 CTTTGAGACTCTTGTT^(m)C_(ks)T_(ks)T_(ks)T_(ds)G_(ds)A_(ds)G_(ds)A_(ds) ^(m) 57 2583C_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ksks)T_(ks)T_(e) 1341502 N/A N/A 2018720202 TATTAGAAGTCAGCCC T_(ks)A_(ks)T_(ks)T_(ds)A_(ds)G_(ds)A_(ds)A_(ds)G32 164 _(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ks) ^(m)C_(ks) ^(m)C_(ks)^(m)C_(e) 1341504 N/A N/A 20197 20212 ACATTGCAGTTATTAG A_(ks)^(m)C_(ks)A_(ks)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(d) 52 2309_(s)G_(ds)T_(ds)T_(ds)A_(ds)T_(ks)T_(ks)A_(ks)G_(e) 1341512 N/A N/A12794 12809 AAGAGTCAGTATCCTC A_(ks)A_(ks)G_(ks)A_(ds)G_(ds)T_(ds)^(m)C_(ds)A_(ds) 67 2572 G_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ks)^(m)C_(ks)T_(ks) ^(m)C_(e) 1341514 N/A N/A 12496 12511 AATTCACCTTGACTAAA_(ks)A_(ks)T_(ks)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C 16 2144_(ds)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks)A_(ks)A_(e) 1341515 N/A N/A12804 12819 CTCAGGCTGTAAGAGT ^(m)C_(ks)T_(ks)^(m)C_(ks)A_(ds)G_(ds)G_(ds) ^(m)C_(ds)T 21 2240_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ks)A_(ks)G_(ks)T_(e)

TABLE 44 Inhibition of HSD17B13 RNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: % SEQ Compound 1 Start1 Stop 2 Start 2 Stop Sequence Chemistry Notation in- ID Number SiteSite Site Site (5′ to 3′) (5′ to 3′) hibition NO 1245927 N/A N/A  3433 3448 AGTAGATGGTAAGTCAA_(ks)G_(ks)T_(ks)A_(ds)G_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 79 121T_(ds)A_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1246023 N/A N/A  5046 5061 GAGTGAATCATTCAGT G_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(d) 83 1526 _(s)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)T_(k)1340981 1495 1510 21310 21325 TTGCACCGTTTTGGGC T_(ks)T_(ks)G_(ks)^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ds) 50 1749T_(ds)T_(ds)T_(ds)T_(ds)G_(ks)G_(ks)G_(ks) ^(m)C_(e) 1340983 1499 151421314 21329 AGAGTTGCACCGTTTT A_(ks)G_(ks)A_(ks)G_(ds)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(d) 78 34 _(s) ^(m)C_(ds)^(m)C_(ds)G_(ds)T_(ks)T_(ks)T_(ks)T_(e) 1340991  810  825 15691 15706TATTGGTAAGTATTCC T_(ks)A_(ks)T_(ks)T_(ds)G_(ds)G_(ds)T_(ds)A_(ds)A_(ds)48 1272 G_(ds)T_(ds)A_(ds)T_(ks)T_(ks) ^(m)C_(ks) ^(m)C_(e) 1340995 16201635 21435 21450 AGTCGGTCACCTTTCA A_(ks)G_(ks)T_(ks)^(m)C_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ds) 75 272 A_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ds)T_(ks)T_(ks) ^(m)C_(ks)A_(e) 1340998 1600 1615 2141521430 GTATCTTATAAGACTA G_(ks)T_(ks)A_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds) 72 1595 A_(ds)A_(ds)G_(ds)A_(ks)^(m)C_(ks)T_(ks)A_(e) 1341000 1624 1639 21439 21454 ATAGAGTCGGTCACCTA_(ks)T_(ks)A_(ks)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)G_(d) 67 584_(s)G_(ds)T_(ds) ^(m)C_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(ks)T_(e) 13410021712 1727 21527 21542 ACATCTCTGGGACCAA A_(ks) ^(m)C_(ks)A_(ks)T_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds) 65 195 G_(ds)G_(ds)G_(ds)A_(ds)^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(e) 1341004 1628 1643 21443 21458TAAAATAGAGTCGGTC T_(ks)A_(ks)A_(ks)A_(ds)A_(ds)T_(ds)A_(ds)G_(ds)A_(ds)74 895 G_(ds)T_(ds) ^(m)C_(ds)G_(ks)G_(ks)T_(ks) ^(m)C_(e) 1341011 17521767 21567 21582 TCCTGTGTTAGCTTTA T_(ks) ^(m)C_(ks)^(m)C_(ks)T_(ds)G_(ds)T_(ds)G_(ds)T_(ds)T 75 1442 _(ds)A_(ds)G_(ds)^(m)C_(ds)T_(ks)T_(ks)T_(ks)A_(e) 1341013 1721 1736 21536 21551ATTGTCTAAACATCTC A_(ks)T_(ks)T_(ks)G_(ds)T_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds) 71 585 A_(ds) ^(m)C_(ds)A_(ds)T_(ks)^(m)C_(ks)T_(ks) ^(m)C_(e) 1341017 1019 1034 20834 20849TGCAGCATTGATTCGA T_(ks)G_(ks) ^(m)C_(ks)A_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ds)T 52 419 _(ds)G_(ds)A_(ds)T_(ds)T_(kss)^(m)C_(ks)G_(ks)A_(e) 1341030 1784 1799 21599 21614 GTTTCTTATGTAATAGG_(ks)T_(ks)T_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)A_(ks)T_(ds) 44 897G_(ds)T_(ds)A_(ds)A_(ks)T_(ks)A_(ks)G_(e) 1341033 2189 2204 22004 22019CTTGATGTAGTGGGAG^(m)C_(ks)T_(ks)T_(ks)G_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 62 976G_(ds)T_(ds)G_(ds)G_(ks)G_(ks)A_(ks)G_(e) 1341039 1780 1795 21595 21610CTTATGTAATAGCCAG^(m)C_(ks)T_(ks)Td_(s)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 70 664T_(ds)A_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(ks)G_(e) 1341042 N/A N/A 9334  9349 CGATCCTATATACATC ^(m)C_(ks)G_(ks)A_(ks)T_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ds)A_(ds) 29 2788 T_(ds)A_(ds)T_(ds)A_(ds)^(m)C_(ks)A_(ks)T_(ks) ^(m)C_(e) 1341043 2252 2267 22067 22082AGAGGATAGTCCATGC A_(ks)G_(ks)A_(ks)G_(ds)G_(ds)A_(ds)T_(ds)A_(ds)G_(ds)78 354 T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)T_(ks)G_(ks) ^(m)C_(e) 13410442353 2368 22168 22183 ATAACTACAAGAGGTT A_(ks)T_(ks)A_(ks)A_(ds)^(m)C_(ds)T_(ds)A_(ds) ^(m)C_(ds) 67 1133A_(ds)A_(ds)G_(ds)A_(ds)G_(ks)G_(ks)T_(ks)T_(e) 1341053 N/A N/A  9968 9983 AGTAGTGTAAGCTGAGA_(ks)G_(ks)T_(ks)A_(ds)G_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 71 2155A_(ds)G_(ds) ^(m)C_(ds)T_(ks)G_(ks)A_(ks)G_(e) 1341056 N/A N/A  9516 9531 ACACTAATATTGAGGC A_(ks) ^(m)C_(ks)A_(ks)^(m)C_(ds)T_(ds)A_(ds)A_(ds)T_(ds) 68 1928A_(ds)T_(ds)T_(ds)G_(ds)A_(ks)G_(ks)G_(ks) ^(m)C_(e) 1341057 N/A N/A 9603  9618 CACATATGTGAAGAGC ^(m)C_(ks)A_(ks)^(m)C_(ks)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)T 74 760_(ds)G_(ds)A_(ds)A_(ds)G_(ks)A_(ks)G_(ks) ^(m)C_(e) 1341060 N/A N/A12421 12436 TGGTAACGGTGATCAA T_(ks)G_(ks)G_(ks)T_(ds)A_(ds)A_(ds)^(m)C_(ds)G_(ds)G_(d) 35 67 _(s)T_(ds)G_(ds)A_(ds)T_(ks)^(m)C_(ks)A_(ks)A_(e) 1341068 N/A N/A 11546 11561 TCTTGACAATGGTTGCT_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds)A 77 2199_(ds)T_(ds)G_(ds)G_(ds)T_(ks)T_(ks)G_(ks) ^(m)C_(e) 1341071 N/A N/A15494 15509 GCATTAATGCCACCCT G_(ks)^(m)C_(ks)A_(ks)T_(ds)T_(ds)A_(ds)A_(ds)T_(ds)G_(d) 51 1012 _(s)^(m)C_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ks)T_(e) 1341075  608  623 N/A N/A ACAATATGGGATGAGG A_(ks)^(m)C_(ks)A_(ks)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(d) 76 1579_(s)G_(ds)A_(ds)T_(ds)G_(ks)A_(ks)G_(ks)G_(e) 1341076 N/A N/A 1491414929 ACATTAGCAAGCTAAG A_(ks) ^(m)C_(ks)A_(ks)T_(ds)T_(ds)A_(ds)G_(ds)^(m)C_(ds) 41 2065 A_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)A_(ks)A_(ks)G_(e)1341077 1080 1095 20895 20910 TGCTAGTGCCAAACCA T_(ks)G_(ks)^(m)C_(ks)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds) ^(m)C 73 1432 _(ds)^(m)C_(ds)A_(ds)A_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 1341081 N/A N/A16223 16238 CTTTTTATAGACTGGG^(m)C_(ks)T_(ks)T_(ks)T_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) 44 857G_(ds)A_(ds) ^(m)C_(ds)T_(ks)G_(ks)G_(ks)G_(e) 1341084 N/A N/A 1638416399 AATCCCAACCAAACTT A_(ks)A_(ks)T_(ks) ^(m)C_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds) 13 2755 ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ks)^(m)C_(ks)T_(ks)T_(e)  1341089 N/A N/A 16129 16144 TCCATAATAATAGCTCT_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A 66 546_(ds)A_(ds)T_(ds)A_(ds)G_(ks) ^(m)C_(ks)T_(ks) ^(m)C_(e) 1341092 N/A N/A18095 18110 AATTGATACACCAATGA_(ks)A_(ks)T_(ks)T_(ds)G_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(d) 53 2525_(s)A_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)A_(ks)T_(ks)G_(e) 1341096 N/A N/A17990 18005 TTAGTATAGTTATCTTT_(ks)T_(ks)A_(ks)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)G_(ds) 45 2366T_(ds)T_(ds)A_(ds)T_(ks) ^(m)C_(ks)T_(ks)T_(e) 1341101 N/A N/A 1990919924 ATCTTAAGATACCCAG A_(ks)T_(ks)^(m)C_(ks)T_(ds)T_(ds)A_(ds)A_(ds)G_(ds)A_(d) 71 397 _(s)T_(ds)A_(ds)^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(ks)G_(e) 1341102 N/A N/A 18693 18708AGACTTTGAGACTCTT A_(ks)G_(ks)A_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)A_(d) 41 2804 _(s)G_(ds)A_(ds)^(m)C_(ds)T_(ks) ^(m)C_(ks)T_(ks)T_(e) 1341103 N/A N/A 19913 19928GTGCATCTTAAGATAC G_(ks)T_(ks)G_(ks) ^(m)C_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds)T 29 2806 _(ds)A_(ds)A_(ds)G_(ds)A_(ks)T_(ks)A_(ks)^(m)C_(e) 1341115 N/A N/A 20190 20205 AGTTATTAGAAGTCAGA_(ks)G_(ks)T_(ks)T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 56 2746A_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(ks)G_(e) 1341118 N/A N/A 2011420129 GCATCAAGACATTCTA G_(ks) ^(m)C_(ks)A_(ks)T_(ds)^(m)C_(ds)A_(ds)A_(ds)G_(ds) 84 1565 A_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ks)^(m)C_(ks)T_(ks)A_(e) 1341120 1084 1099 20899 20914 CTGCTGCTAGTGCCAA^(m)C_(ks)T_(ks)G_(ks) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) 66 1743A_(ds)G_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(e)  1341121 N/AN/A 12499 12514 AGAAATTCACCTTGACA_(ks)G_(ks)A_(ks)A_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(d) 7 2284 _(s)^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ks)G_(ks)A_(ks) ^(m)C_(e) 1341126 N/A N/A20484 20499 CTTCATAGTGGACTTC ^(m)C_(k)T_(ks)T_(ks)^(m)C_(ds)A_(ds)T_(ds)A_(ds)G_(ds)T 57 711 _(ds)G_(ds)G_(ds)A_(ds)^(m)C_(ks)T_(ks)T_(ks) ^(m)C_(e) 1341131 N/A N/A 14196 14211TATGTGATTGAGTTCT T_(ks)A_(ks)T_(ks)G_(ds)T_(ds)G_(ds)A_(ds)T_(ds)T_(ds)43 2367 G_(ds)A_(ds)G_(ds)T_(ks)T_(ks) ^(m)C_(ks)T_(e) 1341137 N/A N/A12797 12812 TGTAAGAGTCAGTATCT_(ks)G_(ks)T_(ks)A_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) 46 2652^(m)C_(ds)A_(ds)G_(ds)T_(ks)A_(ks)T_(ks) ^(m)C_(e) 1341138 N/A N/A 1417214187 TTGAATAGCAAGCCAA T_(ks)T_(ks)G_(ks)A_(ds)A_(ds)T_(ds)A_(ds)G_(ds)^(m)C_(d) 33 1864 _(s)A_(ds)A_(ds)G_(ds) ^(m)C_(ks)^(m)C_(ks)A_(ks)A_(e) 1341143 1261 1276 21076 21091 AGGTAGCTTTTGTCCAA_(ks)G_(ks)G_(ks)T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ds)T_(d) 58 109_(s)T_(ds)T_(ds)G_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 1341145 12561271 21071 21086 GCTTTTGTCCACCTTT G_(ks)^(m)C_(ks)T_(ks)T_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C 81 1744 _(ds)^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks)T_(ks)T_(e) 1341150 13181333 21133 21148 TGAACAGTCTTAAACC T_(ks)G_(ks)A_(ks)A_(ds)^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m) 61 344C_(ds)T_(ds)T_(ds)A_(ds)A_(ks)A_(ks) ^(m)C_(ks) ^(m)C_(e) 1341154 13141329 21129 21144 CAGTCTTAAACCTTCC ^(m)C_(ks)A_(ks)G_(ks)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)A 74 30 _(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ks)T_(ks) ^(m)C_(ks) ^(m)C_(e) 1341160  698  713 1211612131 GAGACATGAGGTTTTG G_(ks)A_(ks)G_(ks)A_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ds)A 61 725_(ds)G_(ds)G_(ds)T_(ds)T_(ks)T_(ks)T_(ks)G_(e) 1341166 1324 1339 2113921154 GCTACTTGAACAGTCT G_(ks) ^(m)C_(ks)T_(ks)A_(ds)^(m)C_(ds)T_(ds)T_(ds)G_(ds)A 60 811 _(ds)A_(ds)^(m)C_(ds)A_(ds)G_(ks)T_(ks) ^(m)C_(ks)T_(e) 1341184 1329 1344 2114421159 GGAATGCTACTTGAAC G_(ks)G_(ks)A_(ks)A_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ds)A_(d) 68 1201 _(s)^(m)C_(ds)T_(ds)T_(ds)G_(ks)A_(ks)A_(ks) ^(m)C_(e) 1341194 1337 135221152 21167 TACAGATTGGAATGCT T_(ks)A_(ks)^(m)C_(ks)A_(ds)G_(ds)A_(ds)T_(ds)T_(ds)G_(d) 66 1746_(s)G_(ds)A_(ds)A_(ds)T_(ks)G_(ks) ^(m)C_(ks)T_(e) 1341266 1349 136421164 21179 CTGTGGCATGGCTACA ^(m)C_(ks)T_(ks)G_(ks)T_(ds)G_(ds)G_(ds)^(m)C_(ds)A_(ds)T 58 657 _(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ks)A_(ks)^(m)C_(ks)A_(e) 1341295 1354 1369 21169 21184 ATATTCTGTGGCATGGA_(ks)T_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds) 58 968G_(ds)G_(ds) ^(m)C_(ds)A_(ks)T_(ks)G_(ks)G_(e) 1341318 1358 1373 2117321188 GTTGATATTCTGTGGCG_(ks)T_(ks)T_(ks)G_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(ds) ^(m) 73 1280C_(ds)T_(ds)G_(ds)T_(ks)G_(ks)G_(ks) ^(m)C_(e) 1341392 1367 1382 2118221197 TGTGTTCTTGTTGATA T_(ks)G_(ks)T_(ks)G_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds) 65 1591 G_(ds)T_(ds)T_(ds)G_(ks)A_(ks)T_(ks)A_(e)1341400  796  811 15677 15692 CCATCTATCAGACTTC ^(m)C_(ks)^(m)C_(ks)A_(ks)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)T_(ds) 60 415^(m)C_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ks)T_(ks)T_(ks) ^(m)C_(e)  13414211420 1435 21235 21250 GGTTGAGATAAAGCTGG_(ks)G_(ks)T_(ks)T_(ds)G_(ds)A_(ds)G_(ds)A_(ds)T_(ds) 67 1826A_(ds)A_(ds)A_(ds)G_(ks) ^(m)C_(ks)T_(ks)G_(e) 1341426 1393 1408 2120821223 TTGATCTCTTAGCTGT T_(ks)T_(ks)G_(ks)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T 64 658 _(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ks)T_(ks)G_(ks)T_(e)1341431 1429 1444 21244 21259 ATATGTCCAGGTTGAGA_(ks)T_(ks)A_(ks)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A 71 425_(ds)G_(ds)G_(ds)T_(ds)T_(ks)G_(ks)A_(ks)G_(e) 1341432 1491 1506 2130621321 ACCGTTTTGGGCTAAT A_(ks) ^(m)C_(ks)^(m)C_(ks)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G 73 1438 _(ds)G_(ds)G_(ds)^(m)C_(ds)T_(ks)A_(ks)A_(ks)T_(e) 1341435 1466 1481 21281 21296AGAGGCTAGGGAAATC A_(ks)Gc_(s)A_(k)G_(ds)G_(ds) ^(m)C_(ds)T_(ds)A_(ds)G68 1048 _(ds)G_(ds)G_(ds)A_(ds)A_(ks)A_(ks)T_(ks) ^(m)C_(e) 1341441 16161631 21431 21446 GGTCACCTTTCATAAT G_(ks)G_(ks)T_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds) ^(m)C_(ds)T_(ds) 49 1985 T_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ks)A_(ks)A_(ks)T_(e) 1341449 1771 1786 21586 21601TAGCCAGTACAGTTCC T_(ks)A_(ks)G_(ks) ^(m)C_(ds)^(m)C_(ds)A_(ds)G_(ds)T_(ds) 58 1987 A_(ds)^(m)C_(ds)A_(ds)G_(ds)T_(ks)T_(ks) ^(m)C_(ks) ^(m)C_(e) 1341451 17761791 21591 21606 TGTAATAGCCAGTACAT_(ks)G_(ks)T_(ks)A_(ds)A_(ds)A_(ds)G_(ds) ^(m)C_(d) 34 352 _(s)^(m)C_(ds)A_(ds)G_(ds)T_(ks)A_(ks) ^(m)C_(ks)A_(e) 1341456 1707 172221522 21537 TCTGGGACCAAGGATA T_(ks)^(m)C_(ks)T_(ks)G_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m) 57 1830C_(ds)A_(ds)A_(ds)G_(ds)G_(ks)A_(ks)T_(ks)A_(e) 1341457 1716 1731 2153121546 CTAAACATCTCTGGGA ^(m)C_(ks)T_(ks)A_(ks)A_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds) ^(m) 57 2259 C_(ds)T_(ds)^(m)C_(ds)T_(ds)G_(ks)G_(ks)G_(ks)A_(e) 1341466 2196 2211 22011 22026GATTAGTCTTGATGTA G_(ks)A_(ks)T_(ks)T_(ds)A_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds) 48 1521 T_(ds)G_(ds)A_(ds)T_(ks)G_(ks)T_(ks)A_(e)1341474 N/A N/A 11578 11593 GTTATTCTCTTGACAAG_(ks)T_(ks)T_(ks)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C 35 2575_(ds)T_(ds)T_(ds)G_(ds)A_(ks) ^(m)C_(ks)A_(ks)A_(e) 1341482 N/A N/A16292 16307 TTAGTTAGAATAGTCTT_(ks)T_(ks)A_(ks)G_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds) 67 1714A_(ds)T_(ds)A_(ds)G_(ks)T_(ks) ^(m)C_(ks)T_(e) 1341488 N/A N/A 1990519920 TAAGATACCCAGGTTG T_(ks)A_(ks)A_(ks)G_(ds)A_(ds)T_(ds)A_(ds)^(m)C_(ds) ^(m) 58 2790 C_(ds)^(m)C_(ds)A_(ds)G_(ds)G_(ks)T_(ks)T_(ks)G_(e) 1341492 1076 1091 2089120906 AGTGCCAAACCAATGT A_(ks)G_(ks)T_(ks)G_(ds) ^(m)C_(ds)^(m)C_(ds)Ad_(s)A_(ds) 60 1120 A_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ks)T_(ks)G_(ks)T_(e) 1341495 N/A N/A 17995 18010TGAAGTTAGTATAGTT T_(ks)G_(ks)A_(ks)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds)G_(ds)70 1405 T_(ds)A_(ds)T_(ds)A_(ks)G_(ks)T_(ks)T_(e) 1341498 N/A N/A 1999920014 CAGTTTTCCTCATGAT ^(m)C_(ks)A_(ks)G_(ks)T_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ds) ^(m) 65 2331 C_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ks)G_(ks)A_(ks)T_(e) 1341500 N/A N/A 20378 20393CACAAGTAAGGTAAAG ^(m)C_(ks)A_(ks)^(m)C_(ks)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 55 2448A_(ds)G_(ds)G_(ds)T_(ds)A_(ks)A_(ks)A_(ks)G_(e) 1341503 N/A N/A 2038820403 CTATAGTAATCACAAG^(m)C_(ks)T_(ks)A_(ks)T_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(d) 53 1644_(s)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ks)A_(ks)A_(ks)G_(e) 1341510 10911106 20906 20921 CGTTTGACTGCTGCTA^(m)C_(ks)G_(ks)T_(ks)T_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ds)T 75 264_(ds)G_(ds) ^(m)C_(ds)T_(ds)G_(ks) ^(m)C_(ks)T_(ks)A_(e) 1341513 N/A N/A13959 13974 GTCTACCTCTAAGTTA G_(ks)T_(ks) ^(m)C_(ks)T_(ds)A_(ds)^(m)C_(ds) ^(m)C_(ds)T_(ds) 41 2363^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ks)T_(ks)T_(ks)A_(e) 1341516 N/A N/A13949 13964 AAGTTAGCCCCCAGGA A_(ks)A_(ks)G_(ks)T_(ds)T_(ds)A_(ds)G_(ds)^(m)C_(ds) ^(m) 23 2811 C_(ds) ^(m)C_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ks)G_(ks)G_(ks)A_(e)

TABLE 45 Inhibition of HSD17B13 RNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ SEQ SEQ SEQ ID NO: ID NO: ID NO: ID NO: % SEQ Compound 1 Start1 Stop 2 Start 2 Stop Sequence Chemistry Notation in- ID Number SiteSite Site Site (5′ to 3′) (5′ to 3′) hibition NO 1245927 N/A N/A  3433 3448 AGTAGATGGTAAGTCAA_(ks)G_(ks)T_(ks)A_(ds)G_(ds)A_(ds)T_(ds)G_(ds)G_(ds)T 79 121_(ds)A_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1246023 N/A N/A  5046 5061 GAGTGAATCATTCAGT G_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds) 80 1526 A_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)T_(k)1340980  610  625 N/A N/A GAACAATATGGGATGA G_(ks)A_(ks)A_(ks)^(m)C_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ds) 52 1735G_(ds)G_(ds)G_(ds)A_(ks)T_(ks)G_(ks)A_(e) 1340985 1492 1507 21307 21322CACCGTTTTGGGCTAA ^(m)C_(ks)A_(ks) ^(m)C_(ks)^(m)C_(ds)G_(ds)T_(ds)T_(ds)T_(ds)T 71 1516 _(ds)G_(ds)G_(ds)G_(ds)^(m)C_(ks)T_(ks)A_(ks)A_(e) 1340986 1501 1516 21316 21331ATAGAGTTGCACCGTT A_(ks)A_(k)G_(ds)A_(ds)G_(ds)T_(ds)T_(ds)G_(ds) ^(m) 71192 _(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ks)T_(ks)A_(ks)A_(e)  1340989  812 827 15693 15708 CTTATTGGTAAGTATT^(m)C_(ks)T_(ks)T_(ks)A_(ds)T_(ds)T_(ds)G_(ds)G_(ds)T_(ds) 24 1350A_(ds)A_(ds)G_(ds)T_(ks)A_(ks)T_(ks)T_(e) 1340992 1621 1636 21436 21451GAGTCGGTCACCTTTC G_(ks)A_(ks)G_(ks)T_(ds) ^(m)C_(ds)G_(ds)G_(ds)T_(ds)^(m)C_(d) 74 350 _(s)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)T_(ks)T_(ks)^(m)C_(e)  1340996 1602 1617 21417 21432 ATGTATCTTATAAGACA_(ks)T_(ks)G_(Ks)T_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ds) 24 1751A_(ds)T_(ds)A_(ds)A_(ks)G_(ks)A_(ks) ^(m)C_(e) 1340999 1617 1632 2143221447 CGGTCACCTTTCATAA ^(m)C_(ks)G_(ks)G_(ks)T_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds) ^(m)C_(ds) 67 36 T_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ks)T_(ks)A_(ks)A_(e) 1341003 1625 1640 21440 21455AATAGAGTCGGTCACC A_(ks)A_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)^(m)C_(ds) 58 662 G_(ds)G_(ds)T_(ds) ^(m)C_(ks)A_(ks) ^(m)C_(ks)^(m)C_(e) 1341007 1629 1644 21444 21459 TTAAAATAGAGTCGGTT_(ks)T_(ks)A_(ks)A_(ds)A_(ds)A_(ds)T_(ds)A_(ds)G_(ds)A 71 973_(ds)G_(ds)T_(ds) ^(m)C_(ks)G_(ks)G_(ks)T_(e) 1341010 1708 1723 2152321538 CTCTGGGACCAAGGAT ^(m)C_(ks)T_(ks)^(m)C_(ks)T_(ds)G_(ds)G_(ds)G_(ds)A_(ds) ^(m)C 62 1908 _(ds)^(m)C_(ds)A_(ds)A_(ds)G_(ks)G_(ks)A_(ks)T_(e) 1341015 1713 1728 2152821543 AACATCTCTGGGACCA A_(ks)A_(ks) ^(m)C_(ks)A_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ds)T 61 273 _(ds)G_(ds)G_(ds)G_(ds)A_(ks)^(m)C_(ks) ^(m)C_(ks)A_(e) 1341021 1773 1788 21588 21603AATAGCCAGTACAGTT A_(ks)A_(ks)T_(ks)A_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)G_(d) 61 118 _(s)T_(ds)A_(ds)^(m)C_(ds)A_(ks)G_(ks)T_(ks)T_(e) 1341022 1781 1796 21596 21611TCTTATGTAATAGCCA T_(ks)^(m)C_(ks)T_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds)A_(ds) 76 742A_(ds)T_(ds)A_(ds)G_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 1341023 1766 178121581 21596 AGTACAGTTCCTTTTC A_(ks)G_(ks)T_(ks)A_(sds) ^(m)_(s)C_(dss)A_(ds)G_(ds)T_(ds)T_(ds) 59 1597 ^(m)C_(ds)^(m)C_(ds)T_(ds)T_(ks)T_(ks)T_(ks) ^(m)C_(e) 1341024 1777 1792 2159221607 ATGTAATAGCCAGTAC A_(ks)T_(ks)G_(ks)T_(ds)A_(ds)A_(ds)T_(ds)G_(ds)^(m) 63 430 C_(ds) ^(m)C_(ds)A_(ds)G_(ks)T_(ks)A_(ks) ^(m)C_(e) 13410342191 2206 22006 22021 GTCTTGATGTAGTGGG G_(ks)T_(ks)^(m)C_(ks)T_(ds)T_(ds)G_(ds)A_(ds)T_(ds)G_(ds) 70 1132T_(ds)A_(ds)G_(ds)T_(ks)G_(ks)G_(ks)G_(e) 1341040 1081 1096 20896 20911CTGCTAGTGCCAAACC ^(m)C_(ks)T_(ks)G_(ks)^(m)C_(ds)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 67 1510 ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ks)A_(ks) ^(m)C_(ks) ^(m)C_(e) 1341045 2254 226922069 22084 CAAGAGGATAGTCCAT^(m)C_(ks)A_(ks)A_(ks)G_(ds)A_(ds)G_(ds)G_(ds)A_(ds)T_(ds) 64 510A_(ds)G_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(ks)T_(e) 1341048 2245 226022060 22075 AGTCCATGCAAAAGCA A_(ks)G_(ks)T_(ks) ^(m)C_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ds) ^(m)C 80 120_(ds)A_(ds)A_(ds)A_(ds)A_(ks)G_(ks) ^(m)C_(ks)A_(e) 1341049 2355 237022170 22185 TTATAACTACAAGAGG T_(ks)T_(ks)A_(ks)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds)A_(ds) ^(m) 43 1289C_(ds)A_(ds)A_(ds)G_(ks)A_(ks)G_(ks)G_(e) 1341051 1077 1092 20892 20907TAGTGCCAAACCAATG T_(ks)A_(ks)G_(ks)T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(d) 61 1198 _(s)A_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ks)A_(ks)T_(ks) 1341059 N/A N/A 9518 9533 CTACACTAATATTGAG^(m)C_(ks)T_(ks)A_(ks) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds)A_(ds)A 10 59_(ds)T_(ds)A_(ds)T_(ds)T_(ks)G_(ks)A_(ks)G_(e) 1341065 N/A N/A 1185311868 AGCAGAATTGTGAACG A_(ks)G_(ks)^(m)C_(ks)A_(ds)G_(ds)A_(ds)A_(ds)T_(ds)T_(ds) 56 844G_(ds)T_(ds)G_(ds)A_(ks)A_(ks) ^(m)C_(ks)G_(e) 1341066 N/A N/A 1242312438 GGTGGTAACGGTGATC G_(ks)G_(ks)T_(ks)G_(ds)G_(ds)T_(ds)A_(ds)A_(ds)^(m)C_(ds) 47 2591 G_(ds)G_(ds)T_(ds)G_(ks)A_(ks)T_(ks) ^(m)C_(e)1341072 N/A N/A 15496 15511 CTGCATTAATGCCACC ^(m)C_(ks)T_(ks)G_(ks)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)A_(ds) 40 1168 T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ks)A_(ks) ^(m)C_(ks) ^(m)C_(e) 1341074 N/A N/A 14197 14212TTATGTGATTGAGTTCT_(ks)T_(ks)A_(ks)T_(ds)G_(ds)T_(ds)G_(ds)A_(ds)T_(ds)T_(d) 30 2431_(s)G_(ds)A_(ds)G_(ks)T_(ks)T_(ks) ^(m)C_(e) 1341078 N/A N/A 14916 14931ATACATTAGCAAGCTA A_(ks)T_(ks)A_(ks)^(m)C_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds) 48 309^(m)C_(ds)A_(ds)A_(ds)G_(ks) ^(m)C_(ks)T_(ks)A_(e) 1341086 N/A N/A 1613116146 GCTCCATAATAATAGC G_(ks) ^(m)C_(ks)T_(ks) ^(m)C_(ds)^(m)C_(ds)A_(ds)T_(ds)A_(ds)A 8 2665_(ds)T_(ds)A_(ds)A_(ds)T_(ks)A_(ks)G_(ks) ^(m)C_(e) 1341091 N/A N/A17991 18006 GTTAGTATAGTTATCTG_(ks)T_(ks)T_(ks)A_(ds)G_(ds)T_(ds)A_(ds)T_(ds)A_(ds)G 71 1171_(ds)T_(ds)T_(ds)A_(ks)T_(ks) ^(m)C_(ks)T_(e) 1341094 N/A N/A 1809718112 GAAATTGATACACCAAG_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)G_(ds)A_(ds)T_(ds)A 64 315 _(ds)^(m)C_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(e) 1341104 N/A N/A 1991019925 CATCTTAAGATACCCA ^(m)C_(ks)A_(ks)T_(ks)^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds)G_(ds) 76 475 A_(ds)T_(ds)A_(ds)^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 1341106 N/A N/A 18695 18710AAAGACTTTGAGACTC A_(ks)A_(ks)A_(ks)G_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 67 1250 G_(ds)A_(ds)G_(ds)A_(ks)^(m)C_(ks)T_(ks) ^(m)C_(e) 1341109 1085 1100 20900 20915ACTGCTGCTAGTGCCA A_(ks) ^(m)C_(ks)T_(ks)G_(ds) ^(m)C_(ds)T_(ds)G_(ds)^(m)C_(ds)T 57 1821 _(ds)A_(ds)G_(ds)T_(ds)G_(ks) ^(m)C_(ks)^(m)C_(ks)A_(e) 1341111 N/A N/A 20116 20131 CAGCATCAAGACATTC^(m)C_(ks)A_(ks)G_(ks) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)A_(ds) 70 2191A_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ks)T_(ks)T_(ks)  1341112 N/A N/A 2038120396 AATCACAAGTAAGGTA A_(ks)A_(ks)T_(ks) ^(m)C_(ds)A_(ds)^(m)C_(ds)A_(ds)A_(ds)G_(d) 63 1333_(s)T_(ds)A_(ds)A_(ds)G_(ks)G_(ks)T_(ks)A_(e) 1341117 N/A N/A 2019220207 GCAGTTATTAGAAGTC G_(ks)^(m)C_(ks)A_(ks)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds)T_(ds) 67 398A_(ds)G_(ds)A_(ds)A_(ks)G_(ks)T_(ks) ^(m)C_(e) 1341124 N/A N/A 1250112516 GCAGAAATTCACCTTG G_(ks)^(m)C_(ks)A_(ks)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds) 62 1002^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks)T_(ks)G_(e) 1341128 N/A N/A20486 20501 AACTTCATAGTGGACT A_(ks)A_(ks) ^(m)C_(ks)T_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ds)A_(ds) 70 2555 G_(ds)T_(ds)G_(ds)G_(ks)A_(ks)^(m)C_(ks)T_(e) 1341129 N/A N/A 20422 20437 ACAGTAAAATTATGCC A_(ks)^(m)C_(ks)A_(ks)G_(ds)T_(ds)A_(ds)A_(ds)A_(ds)A_(ds) 62 477T_(ds)T_(ds)A_(ds)T_(ks)G_(ks) ^(m)C_(ks) ^(m)C_(e) 1341135 N/A N/A13952 13967 TCTAAGTTAGCCCCCA T_(ks)^(m)C_(ks)T_(ks)A_(ds)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds) 0 928 G_(ds)^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(e) 1341139 N/AN/A 12799 12814 GCTGTAAGAGTCAGTA G_(ks)^(m)C_(ks)T_(ks)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 52 693 G_(ds)T_(ds)^(m)C_(ds)A_(ks)G_(ks)T_(ks)A_(e) 1341140 1180 1195 20995 21010GTTTTTAAGAGGCATGG_(ks)T_(ks)T_(ks)T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)G_(ds)A_(d) 78 1199_(s)G_(ds)G_(ds) ^(m)C_(ks)A_(ks)T_(ks)G_(e) 1341142 1257 1272 2107221087 AGCTTTTGTCCACCTT A_(ks)G_(ks)^(m)C_(ks)T_(ds)T_(ds)T_(ds)T_(ds)G_(ds)T_(ds) ^(m) 69 1822 C_(ds)^(m)C_(ds) ^(m)C_(ks)T_(ks)T_(ks) ^(m)C_(e)  1341151 1315 1330 2113021145 ACAGTCTTAAACCTTC A_(ks) ^(m)C_(ks)A_(ks)G_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds) 73 110 A_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ks)T_(ks)T_(ks) ^(m)C_(e) 1341153 1325 1340 21140 21155TGCTACTTGAACAGTC T_(ks)C_(ks) ^(m)C_(ks)T_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds)G_(ds) 68  889 A_(ds)A_(ds)^(m)C_(ds)A_(ks)G_(ks)T_(ks) ^(m)C_(e) 1341156 1311 1326 21126 21141TCTTAAACCTTCCCTG T_(ks) ^(m)C_(ks)T_(ks)T_(ds)A_(ds)A_(ds)A_(ds)^(m)C_(ds) ^(m)C 38 2160 _(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)^(m)C_(ks)T_(ks)G_(e) 1341158  700  715 12118 12133 CAGAGACATGAGGTTT^(m)C_(ks)A_(ks)G_(ks)A_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(d) 45 2319_(s)G_(ds)A_(ds)G_(ds)G_(ks)T_(ks)T_(ks)T_(e) 1341167 1321 1336 2113621151 ACTTGAACAGTCTTAA A_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ds)A_(ds)A_(ds)^(m)C_(ds)A_(d) 60 578 _(s)G_(ds)T_(ds)^(m)C_(ds)T_(ks)T_(ks)A_(ks)A_(e) 1341173 1331 1346 21146 21161TTGGAATGCTACTTGA T_(ks)T_(ks)G_(ks)G_(ds)A_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ds) 56 1279 T_(ds)A_(ds) ^(m)C_(ds)T_(ks)T_(ks)G_(ks)A_(e)1341232 1340 1355 21155 21170 GGCTACAGATTGGAAT G_(ks)G_(ks)^(m)C_(ks)T_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds)A_(d) 28 1980_(s)T_(ds)T_(ds)G_(ds)G_(ks)A_(ks)A_(ks)T_(e) 1341255 1351 1366 2116621181 TTCTGTGGCATGGCTA T_(ks)T_(ks)^(m)C_(ks)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ds)  59 812A_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)T_(ks)A_(e) 1341271 1355 1370 2117021185 GATATTCTGTGGCATG G_(ks)A_(ks)T_(ks)A_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ds)G_(ds) 71 1046 T_(ds)G_(ds)G_(ds)^(m)C_(ks)A_(ks)T_(ks)G_(e) 1341321 1359 1374 21174 21189TGTTGATATTCTGTGGT_(ks)G_(ks)T_(ks)T_(ds)G_(ds)A_(ds)T_(ds)A_(ds)T_(ds)T_(d) 64 1358 _(s)^(m)C_(ds)T_(ds)G_(ks)T_(ks)G_(ks)G_(e) 1341323  798  813 15679 15694TTCCATCTATCAGACT T_(ks)T_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds)A 43 571 _(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ks)A_(ks)^(m)C_(ks)T_(e) 1341427 1395 1410 21210 21225 ACTTGATCTCTTAGCT A_(ks)^(m)C_(ks)T_(ks)T_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) 59 813^(m)C_(ds)T_(ds)T_(ds)A_(ks)G_(ks) ^(m)C_(ks)T_(e) 1341428 1387 140221202 21217 TCTTAGCTGTGCACTC T_(ks) ^(m)C_(ks)T_(ks)T_(ds)A_(ds)G_(ds)^(m)C_(ds)T_(ds)G_(ds)  52 190 T_(ds)G_(ds) ^(m)C_(ds)A_(ks)^(m)C_(ks)T_(ks) ^(m)C_(e) 1341436 1421 1436 21236 21251AGGTTGAGATAAAGCT A_(ks)G_(ks)G_(ks)T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)A_(ds)T71 1904 _(ds)A_(ds)A_(ds)A_(ks)G_(ks) ^(m)C_(ks)T_(e) 1341437 1431 144621246 21261 AAATATGTCCAGGTTGA_(ks)A_(ks)A_(ks)T_(ds)A_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 74 581^(m)C_(ds)A_(ds)G_(ds)G_(ks)T_(ks)T_(ks)G_(e) 1341446 1488 1503 2130321318 GTTTTGGGCTAATGAA G_(ks)T_(ks)T_(ks)T_(ds)T_(ds)G_(ds)G_(ds)G_(ds)^(m)C_(ds) 47 1204 T_(ds)A_(ds)A_(ds)T_(ks)G_(ks)A_(ks)A_(e) 13414471496 1511 21311 21326 GTTGCACCGTTTTGGG G_(ks)T_(k)j_(ks)G_(ds)^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)G 45 1827_(ds)T_(ds)T_(ds)T_(ds)T_(ks)G_(ks)G_(ks)G_(e) 1341450 1726 1741 2154121556 CTAAAATTGTCTAAAC^(m)C_(ks)T_(ks)A_(ks)A_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds) 7 2590 T_(ds)^(m)C_(ds)T_(ds)A_(ks)A_(ks)A_(ks) ^(m)C_(e) 1341454 1022 1037 2083720852 CTTTGCAGCATTGATT ^(m)C_(ks)T_(ks)TIc_(s)T_(ds)G_(ds)^(m)c_(ds)A_(ds)G_(ds) ^(m)C 56 2463_(ds)A_(ds)T_(ds)T_(ds)G_(ks)A_(ks)T_(ks)T_(e) 1341455 1717 1732 2153221547 TCTAAACATCTCTGGG T_(ks) ^(m)C_(ks)T_(ks)A_(ds)A_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds)  42 2287 ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ks)G_(ks)G_(ks)G_(e) 1341460 N/A N/A 9337 9352CCTCGATCCTATATAC ^(m)C_(ks) ^(m)C_(ks)T_(ks)^(m)C_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds) 11 2812^(m)C_(ds)T_(ds)A_(ds)T_(ds)A_(ks)T_(ks)A_(ks) ^(m)C_(e) 1341467 21842199 21999 22014 TGTAGTGGGAGTCGGAT_(ks)G_(ks)T_(ks)A_(ds)G_(ds)T_(ds)G_(ds)G_(ds)G_(ds)A 53 587_(ds)G_(ds)T_(ds) ^(m)C_(ks)G_(ks)G_(ks)A_(e) 1341469 N/A N/A 9971 9986TTGAGTAGTGTAAGCT T_(ks)T_(ks)G_(ks)A_(ds)G_(ds)T_(ds)A_(ds)G_(ds)T_(ds)G40 2346 _(ds)T_(ds)A_(ds)A_(ks)G_(ks) ^(m)C_(ks)T_(e) 1341476 N/A N/A11568 11583 TGACAATGGTTGATAG T_(ks)G_(ks)A_(ks)^(m)C_(ds)A_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 38 1700T_(ds)T_(ds)G_(ds)A_(ks)T_(ks)A_(ks)G_(e) 1341477 N/A N/A 9961 9976TAAGCTGAGAGTTCTA T_(ks)A_(ks)A_(ks)G_(ds)^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds) 48 2499 A_(ds)G_(ds)T_(ds)T_(ks)^(m)C_(ks)T_(ks)A_(e) 1341479 N/A N/A 17986 18001 TATAGTTATCTTCTCAT_(ks)A_(ks)T_(ks)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds)T_(ds) ^(m) 59 2295C_(ds)T_(ds)T_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(ks)A_(e) 1341481 N/A N/A17996 18011 ATGAAGTTAGTATAGTA_(ks)T_(ks)G_(ks)A_(ds)A_(ds)G_(ds)T_(ds)T_(ds)A_(ds)G 61 1483_(ds)T_(ds)A_(ds)T_(ks)A_(ks)G_(ks)T_(e) 1341483 N/A N/A 16282 16297TAGTCTTCAGCAAAGT T_(ks)A_(ks)Gr_(ks)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) 36 2632 G_(ds) ^(m)C_(ds)A_(ds)A_(ks)A_(ks)G_(ks)T_(e)1341484 N/A N/A 16377 16392 ACCAAACTTCCAGCAG A_(ks) ^(m)C_(ks)^(m)C_(ks)A_(ds)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)T 36 1948 _(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)G_(ks) ^(m)C_(ks)A_(ks)G_(e) 1341493 N/A N/A 19914 19929AGTGCATCTTAAGATA A_(ks)G_(ks)T_(ks)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds) 12 2130 T_(ds)A_(ds)A_(ds)G_(ks)A_(ks)T_(ks)A_(e)1341505 N/A N/A 19906 19921 TTAAGATACCCAGGTTT_(ks)T_(ks)A_(ks)A_(ds)G_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds) 51 163^(m)C_(ds) ^(m)C_(ds)A_(ds)G_(ks)G_(ks)T_(ks)T_(e) 1341507 N/A N/A 2000920024 AGAGAGTAATCAGTTTA_(ks)G_(ks)A_(ks)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds)T 51 2651 _(ds)^(m)C_(ds)A_(ds)G_(ks)T_(ks)T_(ks)T_(e) 1341509 N/A N/A 14165 14180GCAAGCCAACAGAGAG G_(ks) ^(m)C_(ks)A_(ks)A_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds) 38 2556 A_(ds)^(m)C_(ds)A_(ds)G_(ds)A_(ks)G_(ks)A_(ks)G_(e) 1341511 N/A N/A 1417514190 GCCTTGAATAGCAAGC G_(ks) ^(m)C_(ks)^(m)C_(ks)T_(ds)T_(ds)G_(ds)A_(ds)A_(ds)T_(ds) 38 2063 A_(ds)G_(ds)^(m)C_(ds)A_(ks)A_(ks)G_(ks) ^(m)C_(e)

TABLE 46Inhibition of HSD17B13 RNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 Compound Start StopStart Stop Chemistry Notation % SEQ ID Number Site Site Site SiteSequence (5′ to 3′) (5′ to 3′) inhibition NO 1245927 N/A N/A 3433 3448AGTAGATGGTAAGTCA A_(ks)G_(ks)T_(ks)A_(ds)G_(ds)A_(ds)T_(ds)G_(ds)G_(ds)79 121 T_(ds)A_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1246023 N/A N/A5046 5061 GAGTGAATCATTCAGTG_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds)A_(ds)T_(ds) ^(m)C_(ds) 87 1526A_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)T_(k) 1341648 1251 1266 2106621081 TGTCCACCTTTAAATG T_(ks)G_(kS)T_(ks) ^(m)C_(ds)C_(ys)A_(ds)^(m)C_(ds) ^(m)C_(ds) 17 1666T_(ds)T_(ds)T_(ds)A_(ds)A_(ds)A_(ks)T_(ks)G_(k) 1341654 1317 1332 2113221147 GAACAGTCTTAAACCT G_(ks)A_(ks)A_(ks) ^(m)C_(ds)A_(ys)G_(ds)T_(ds)^(m)C_(ds) 75 266 T_(ds)T_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ks)^(m)C_(ks)T_(k) 1341658 1313 1328 21128 21143 AGTCUTAAACCTTCCCA_(ks)G_(ks)T_(ks) ^(m)C_(ds)U_(ys)T_(ds)A_(ds)A_(ds)A_(ds) 52 2813^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(k)1341661 1321 1336 21136 21151 ACTTGAACAGTCTTAA A_(ks)^(m)C_(ks)T_(ks)T_(ds)G_(ys)A_(ds)A_(ds) ^(m)C_(ds) 29 578A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ks)A_(ks)A_(k) 1341663 1308 132321123 21138 TAAACCTTCCCTGTGT T_(ks)A_(ks)A_(ks)A_(ds)C_(ys)^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds) 46 1745 ^(m)C_(ds)^(m)C_(ds)T_(ds)G_(ds)T_(ks)G_(ks)T_(k) 1341668 1335 1350 21150 21165CAGAUTGGAATGCTAC^(m)C_(ks)A_(ks)G_(ks)A_(ds)U_(ys)T_(ds)G_(ds)G_(ds)A_(ds) 70 2814A_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ks)A_(ks) ^(m)C_(k) 1341672 1329 134421144 21159 GGAAUGCTACTTGAAC G_(ks)G_(ks)A_(ks)A_(ds)U_(ys)G_(ds)^(m)C_(ds)T_(ds) 62 2815 A_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ks)A_(ks)^(m)C_(k) 1341677 1325 1340 21140 21155 TGCTACTTGAACAGTC T_(ks)G_(ks)^(m)C_(ks)T_(ds)A_(ys) ^(m)C_(ds)T_(ds)T_(ds) 65 889 G_(ds)A_(ds)A_(ds)^(m)C_(ds)A_(ds)G_(ks)T_(ks) ^(m)C_(k) 1341685 1342 1357 21157 21172ATGGCTACAGATTGGA A_(ks)T_(ks)G_(ks)G_(ds)C_(ys)T_(ds)A_(ds)^(m)C_(ds)A_(ds) 44 111 G_(ds)A_(ds)T_(ds)T_(ds)G_(ks)G_(ks)A_(k)1341691 1357 1372 21172 21187 TTGAUATTCTGTGGCAT_(ks)T_(ks)G_(ks)A_(ds)U_(ys)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) 60 2816T_(ds)G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)A_(k) 1341692 1348 1363 2116321178 TGTGGCATGGCTACAG T_(ks)G_(ks)T_(ks)G_(ds)G_(ys)^(m)C_(ds)A_(ds)T_(ds)G_(ds) 5 579 G_(ds) ^(m)C_(ds)T_(ds)A_(ds)^(m)C_(ks)A_(ks)G_(k) 1341697 1353 1368 21168 21183 TATTCTGTGGCATGGCT_(ks)A_(ks)T_(ks)T_(ds)C_(ys)T_(ds)G_(ds)T_(ds)G_(ds) 55 890 G_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ks)G_(ks) ^(m)C_(k) 1341698 1366 1381 2118121196 GTGTUCTTGTTGATAT G_(ks)T_(ks)G_(ks)T_(ds)U_(ys)^(m)C_(ds)T_(ds)T_(ds)G_(ds) 52 2817T_(ds)T_(ds)G_(ds)A_(ds)T_(ks)A_(ks)T_(k) 1341702 1394 1409 21209 21224CTTGATCTCTTAGCTG ^(m)C_(ks)T_(ks)T_(ks)G_(ds)A_(ys)T_(ds)^(m)C_(ds)T_(ds) 32 736 ^(m)C_(ds)T_(ds)T_(ds)A_(ds)G_(ds)^(m)C_(ks)T_(ks)G_(k) 1341703 1388 1403 21203 21218 CTCTUAGCTGTGCACT^(m)C_(ks)T_(ks) ^(m)C_(ks)T_(ds)U_(ys)A_(ds)G_(ds) ^(m)C_(ds) 67 2818T_(ds)G_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ks) ^(m)C_(ks)T_(k) 1341713 14211436 21236 21251 AGGTUGAGATAAAGCTA_(ks)G_(ks)G_(ks)T_(ds)U_(ys)G_(ds)A_(ds)G_(ds)A_(ds) 58 2819T_(ds)A_(ds)A_(ds)A_(ds)G_(ks) ^(m)C_(ks)T_(k) 1341716 696 711 1211412129 GACAUGAGGTTTTGAT G_(ks)A_(ks)^(m)C_(ks)A_(ds)U_(ys)G_(ds)A_(ds)G_(ds) 34 2820G_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ks)A_(ks)T_(k) 1341719 1416 1431 2123121246 GAGAUAAAGCTGCCTGG_(ks)A_(ks)G_(ks)A_(ds)U_(ys)A_(ds)A_(ds)A_(ds)G_(ds) 39 2821^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks)G_(k) 1341726 14261441 21241 21256 TGTCCAGGTTGAGATA T_(ks)G_(ks)T_(ks)^(m)C_(ds)C_(ys)A_(ds)G_(ds)G_(ds)T_(ds) 41 191T_(ds)G_(ds)A_(ds)G_(ds)A_(ks)T_(ks)A_(k) 1341727 1464 1479 21279 21294AGGCUAGGGAAATCTT A_(ks)G_(ks)G_(ks) ^(m)C_(ds)U_(ys)A_(ds)G_(ds)G_(ds)41 2822 G_(ds)A_(ds)A_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(ks)T_(k) 13417291494 1509 21309 21324 TGCACCGTTTTGGGCT T_(ks)G_(ks)^(m)C_(ks)A_(ds)C_(ys) ^(m)C_(ds)G_(ds)T_(ds) 55 1671T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)G_(ks) ^(m)C_(ks)T_(k) 1341734 1490 150521305 21320 CCGTUTTGGGCTAATG ^(m)C_(ks)^(m)C_(ks)G_(ks)T_(ds)U_(ys)T_(ds)T_(ds)G_(ds) 51 2823 G_(ds)G_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ks)T_(ks)G_(k) 1341739 1623 1638 21438 21453TAGAGTCGGTCACCTT T_(ks)A_(ks)G_(ks)A_(ds)G_(ys)T_(ds)^(m)C_(ds)G_(ds)G_(ds) 55 506 T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ks)T_(ks)T_(k) 1341743 1598 1613 21413 21428 ATCTUATAAGACTATAA_(ks)T_(ks) ^(m)C_(ks)T_(ds)U_(ys)A_(ds)T_(ds)A_(ds)A_(ds) 35 2824G_(ds)A_(ds) ^(m)C_(ds)T_(ds)A_(ks)T_(ks)A_(k) 1341745 1498 1513 2131321328 GAGTUGCACCGTTTTG G_(ks)A_(ks)G_(ks)T_(ds)U_(ys)G_(ds)^(m)C_(ds)A_(ds) 63 2825 ^(m)C_(ds)^(m)C_(ds)G_(ds)T_(ds)T_(ds)T_(ks)T_(ks)G_(k) 1341753 1615 1630 2143021445 GTCACCTTTCATAATG G_(ks)T_(ks) ^(m)C_(ks)A_(ds)C_(ys)^(m)C_(ds)T_(ds)T_(ds) 40 1907 T_(ds)^(m)C_(ds)A_(ds)T_(ds)A_(ds)A_(ks)T_(ks)G_(k) 1341755 1619 1634 2143421449 GTCGGTCACCTTTCAT G_(ks)T_(ks) ^(m)C_(ks)G_(ds)G_(ys)T_(ds)^(m)C_(ds)A_(ds) 66 194 ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ks)A_(ks)T_(k) 1341758 1627 1642 21442 21457 AAAAUAGAGTCGGTCAA_(ks)A_(ks)A_(ks)A_(ds)U_(ys)A_(ds)G_(ds)A_(ds)G_(ds) 62 2826 T_(ds)^(m)C_(ds)G_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1341759 1711 1726 2152621541 CATCUCTGGGACCAAG ^(m)C_(ks)A_(ks)T_(ks) ^(m)C_(ds)U_(ys)^(m)C_(ds)T_(ds)G_(ds) 42 2827 G_(ds)G_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ks)A_(ks)G_(k) 1341763 1715 1730 21530 21545TAAACATCTCTGGGAC T_(ks)A_(ks)A_(ks)A_(ds)C_(ys)A_(ds)T_(ds)^(m)C_(ds)T_(ds) 49 351 ^(m)C_(ds)T_(ds)G_(ds)G_(ds)G_(ks)A_(ks)^(m)T_(k) 1341774 1705 1720 21520 21535 TGGGACCAAGGATATAT_(ks)G_(ks)G_(ks)G_(ds)A_(ys) ^(m)C_(ds) ^(m)C_(ds)A_(ds) 51 1674A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)A_(ks)T_(ks)A_(k) 1341777 796 811 1567715692 CCATCTATCAGACTTC ^(m)C_(ks)^(m)C_(ks)A_(ks)T_(ds)C_(ys)T_(ds)A_(ds)T_(ds) 56 415^(m)C_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ks)T_(ks) ^(m)C_(k) 13417801770 1785 21585 21600 AGCCAGTACAGTTCCT A_(ks)G_(ks) ^(m)C_(ks)^(m)C_(ds)A_(ys)G_(ds)T_(ds)A_(ds) 65 1909^(m)C_(ds)A_(ds)G_(ds)T_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 13417851751 1766 21566 21581 CCTGUGTTAGCTTTAA ^(m)C_(ks)^(m)C_(ks)T_(ks)G_(ds)U_(ys)G_(ds)T_(ds)T_(ds) 28 2828 A_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ks)A_(ks)A_(k) 1341786 1719 1734 21534 21549TGTCUAAACATCTCTG T_(ks)G_(ks)T_(ks) ^(m)C_(ds)U_(ys)A_(ds)A_(ds)A_(ds)44 2829 ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(ks)G_(k)1341788 1783 1798 21598 21613 TTTCUTATGTAATAGC T_(ks)T_(ks)T_(ks)^(m)C_(ds)U_(ys)T_(ds)A_(ds)T_(ds)G_(ds) 50 2830T_(ds)A_(ds)A_(ds)T_(ds)A_(ks)G_(ks) ^(m)C_(k) 1341793 1775 1790 2159021605 GTAAUAGCCAGTACAG G_(ks)T_(ks)A_(ks)A_(ds)U_(ys)A_(ds)G_(ds)^(m)C_(ds) 62 2831 ^(m)C_(ds)A_(ds)G_(ds)T_(ds)A_(ds)^(m)C_(ks)A_(ks)G_(k) 1341796 1779 1794 21594 21609 TTATGTAATAGCCAGTT_(ks)T_(ks)A_(ks)T_(ds)G_(ys)T_(ds)A_(ds)A_(ds)T_(ds) 56 586A_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)G_(ks)T_(k) 1341800 2187 220222002 22017 TGATGTAGTGGGAGTCT_(ks)G_(ks)A_(ks)T_(ds)G_(ys)T_(ds)A_(ds)G_(ds)T_(ds) 43 820G_(ds)G_(ds)G_(ds)A_(ds)G_(ks)T_(ks) ^(m)C_(k) 1341805 2194 2209 2200922024 TTAGUCTTGATGTAGT T_(ks)T_(ks)A_(ks)G_(ds)U_(ys)^(m)C_(ds)T_(ds)T_(ds)G_(ds) 50 2832A_(ds)T_(ds)G_(ds)T_(ds)A_(ks)G_(ks)T_(k) 1341809 2350 2365 22165 22180ACTACAAGAGGTTATT A_(ks)^(m)C_(ks)T_(ks)A_(ds)C_(ys)A_(ds)A_(ds)G_(ds)A_(ds) 29 899G_(ds)G_(ds)T_(ds)T_(ds)A_(ks)T_(ks)T_(k) 1341810 2250 2265 22065 22080AGGAUAGTCCATGCAA A_(ks)G_(ks)G_(ks)A_(ds)U_(ys)A_(ds)G_(ds)T_(ds) 552833 ^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ks)A_(ks)A_(k)1341822 N/A N/A 9514 9529 ACTAATATTGAGGCAC A_(ks)^(m)C_(ks)T_(ks)A_(ds)A_(ys)T_(ds)A_(ds)T_(ds)T_(ds) 42 1772G_(ds)A_(ds)G_(ds)G_(ds) ^(m)C_(ks)A_(ks) ^(m)C_(k) 1341825 N/A N/A 93329347 ATCCUATATACATCCA A_(ks)T_(ks) ^(m)C_(ks)^(m)C_(ds)U_(ys)A_(ds)T_(ds)A_(ds) 64 2834 T_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(k) 1341828 N/A N/A 96019616 CATAUGTGAAGAGCTG^(m)C_(ks)A_(ks)T_(ks)A_(ds)U_(ys)G_(ds)T_(ds)G_(ds)A_(ds) 39 2835A_(ds)G_(ds)A_(ds)G_(ds) ^(m)C_(ks)T_(ks)G_(k) 1341831 N/A N/A 1157811593 GTTAUTCTCTTGACAA G_(ks)T_(ks)T_(ks)A_(ds)U_(ys)T_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ds) 29 2836 T_(ds)T_(ds)G_(ds)A_(ds)^(m)C_(ks)A_(ks)A_(k) 1341833 N/A N/A 9966 9981 TAGTGTAAGCTGAGAGT_(ks)A_(ks)G_(ks)T_(ds)G_(ys)T_(ds)A_(ds)A_(ds)G_(ds) 31 1852^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ks)A_(ks)G_(k) 1341836 808 823 1568915704 TTGGUAAGTATTCCATT_(ks)T_(ks)G_(ks)G_(ds)U_(ys)A_(ds)A_(ds)G_(ds)T_(ds) 13 2837A_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)T_(k) 1341839 N/A N/A11546 11561 TCTTGACAATGGTTGC T_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ys)A_(ds)^(m)C_(ds)A_(ds)A_(ds) 67 2199 T_(ds)G_(ds)G_(ds)T_(ds)T_(ks)G_(ks)^(m)C_(k) 1341850 N/A N/A 14197 14212 TTATGTGATTGAGTTCT_(ks)T_(ks)A_(ks)T_(ds)G_(ys)T_(ds)G_(ds)A_(ds)T_(ds)T_(ds) 35 2431G_(ds)A_(ds)G_(ds)T_(ks)T_(ks) ^(m)C_(k) 1341856 N/A N/A 12419 12434GTAACGGTGATCAAAT G_(ks)T_(ks)A_(ks)A_(ds)C_(ys)G_(ds)G_(ds)T_(ds)G_(ds)21 2345 A_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ks)A_(ks)T_(k) 1341863 N/A N/A15496 15511 CTGCATTAATGCCACC ^(m)C_(ks)T_(ks)G_(ks)^(m)C_(ds)A_(ys)T_(ds)T_(ds)A_(ds)A_(ds) 52 1168 T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(k) 1341864 1017 1032 20832 20847CAGCATTGATTCGAAA ^(m)C_(ks)A_(ks)G_(ks)^(m)C_(ds)A_(ys)T_(ds)T_(ds)G_(ds) 37 263 A_(ds)T_(ds)T_(ds)^(m)C_(ds)G_(ds)A_(ks)A_(ks)A_(k) 1341867 N/A N/A 14916 14931ATACATTAGCAAGCTA A_(ks)T_(ks)A_(ks)^(m)C_(ds)A_(ys)T_(ds)T_(ds)A_(ds)G_(ds) 36 309^(m)C_(ds)A_(ds)A_(ds)G_(ds) ^(m)C_(ks)T_(ks)A_(k) 1341871 N/A N/A 1628916304 GTTAGAATAGTCTTCAG_(ks)T_(ks)T_(ks)A_(ds)G_(ys)A_(ds)A_(ds)T_(ds)A_(ds) 42 1481G_(ds)T_(ds)T_(ds)T_(ds)T_(ks)T_(ks)A_(k) 1341873 N/A N/A 16218 16233TATAGACTGGGTAGGA T_(ks)A_(ks)T_(ks)A_(ds)G_(ys)A_(ds)^(m)C_(ds)T_(ds)G_(ds) 30 2808 G_(ds)G_(ds)T_(ds)A_(ds)G_(ks)G_(ks)A_(k)1341876 N/A N/A 16127 16142 CATAATAATAGCTCTA^(m)C_(ks)A_(ks)T_(ks)A_(ds)A_(ys)T_(ds)A_(ds)A_(ds)T_(ds) 33 2511A_(ds)G_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(ks)A_(k) 1341878 N/A N/A16382 16397 TCCCAACCAAACTTCC T_(ks) ^(m)C_(ks) ^(m)C_(ks)^(m)C_(ds)A_(ys)A_(ds) ^(m)C_(ds) 43 2026 ^(m)C_(ds)A_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(k) 1341885 N/A N/A 17994 18009GAAGUTAGTATAGTTA G_(ks)A_(ks)A_(ks)G_(ds)U_(ys)T_(ds)A_(ds)G_(ds)T_(ds)43 2838 A_(ds)T_(ds)A_(ds)G_(ds)T_(ks)T_(ks)A_(k) 1341892 1083 109820898 20913 TGCTGCTAGTGCCAAA T_(ks)G_(ks) ^(m)C_(ks)T_(ds)G_(ys)^(m)C_(ds)T_(ds)A_(ds) 50 1665 G_(ds)T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ks)A_(ks)A_(k) 1341893 N/A N/A 17989 18004 TAGTATAGTTATCTTCT_(ks)A_(ks)G_(ks)T_(ds)A_(ys)T_(ds)A_(ds)G_(ds)T_(ds) 13 1093T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ks)T_(ks) ^(m)C_(k) 1341898 N/A N/A19912 19927 TGCAUCTTAAGATACC T_(ks)G_(ks) ^(m)C_(ks)A_(ds)U_(ys)^(m)C_(ds)T_(ds)T_(ds) 51 2839 A_(ds)A_(ds)G_(ds)A_(ds)T_(ds)A_(ks)^(m)C_(ks) ^(m)C_(k) 1341903 N/A N/A 18690 18705 CTTTGAGACTCTTGTT^(m)C_(ks)T_(ks)T_(ks)T_(ds)G_(ys)A_(ds)G_(ds)A_(ds) 15 2583^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ks)T_(ks)T_(k) 1341905 N/A N/A18092 18107 TGATACACCAATGCAG T_(ks)G_(ks)A_(ks)T_(ds)A_(ys)^(m)CdsA_(ds) ^(m)C_(ds) 38 2370 ^(m)C_(ds)A_(ds)A_(ds)T_(ds)G_(ds)^(m)C_(ks)A_(ks)G_(k) 1341910 N/A N/A 19904 19919 AAGAUACCCAGGTTGCA_(ks)A_(ks)G_(ks)A_(ds)U_(ys)A_(ds) ^(m)C_(ds) ^(m)C_(ds) 37 2840^(m)C_(ds)A_(ds)G_(ds)G_(ds)T_(ds)T_(ks)G_(ks) ^(m)C_(k) 1341913 608 623N/A N/A ACAAUATGGGATGAGG A_(ks)^(m)C_(ks)A_(ks)A_(ds)U_(ys)A_(ds)T_(ds)G_(ds) 70 2841G_(ds)G_(ds)A_(ds)T_(ds)G_(ds)A_(ks)G_(ks)G_(k) 1341916 N/A N/A 1990819923 TCTTAAGATACCCAGG T_(ks)^(m)C_(ks)T_(ks)T_(ds)A_(ys)A_(ds)G_(ds)A_(ds)T_(ds) 51 319 A_(ds)^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)G_(ks)G_(k) 1341918 N/A N/A 1991619931 GGAGUGCATCTTAAGA G_(ks)G_(ks)A_(ks)G_(ds)U_(ys)G_(ds)^(m)C_(ds)A_(ds) 32 2842 T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ks)G_(ks)A_(k) 1341920 N/A N/A 2011220127 ATCAAGACATTCTAGC A_(ks)T_(ks) ^(m)C_(ks)A_(ks)A_(ys)G_(ds)A_(ds)^(m)C_(ds) 37 1488 A_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ks)G_(ks)^(m)C_(k) 1341927 1079 1094 20894 20909 GCTAGTGCCAAACCAA G_(ks)^(m)C_(ks)T_(ks)A_(ds)G_(ys)T_(ds)G_(ds) ^(m)C_(ds) 65 1354^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)A_(k) 1341929N/A N/A 20385 20400 TAGTAATCACAAGTAAT_(ks)A_(ks)G_(ks)T_(ds)A_(ys)A_(ds)T_(ds) ^(m)C_(ds)A_(ds) 38 1489^(m)C_(ds)A_(ds)A_(ds)G_(ds)T_(ks)A_(ks)A_(k) 1341931 N/A N/A 2019720212 ACATUGCAGTTATTAG A_(ks) ^(m)C_(ks)A_(ks)T_(ds)U_(ys)G_(ds)^(m)C_(ds)A_(ds) 26 2843 G_(ds)T_(ds)T_(ds)A_(ds)T_(ds)T_(ks)A_(ks)G_(k)1341936 N/A N/A 20187 20202 TATTAGAAGTCAGCCCT_(ks)A_(ks)T_(ks)T_(ds)A_(ys)G_(ds)A_(ds)A_(ds)G_(ds) 29 164 T_(ds)^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(k) 1341940 N/A N/A20482 20497 TCATAGTGGACTTCAT T_(ks)^(m)C_(ks)A_(ks)T_(ds)A_(ys)G_(ds)T_(ds)G_(ds)G_(ds) 44 633 A_(ds)^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ks)A_(ks)T_(k) 1341946 1075 1090 2089020905 GTGCCAAACCAATGTT G_(ks)T_(ks)G_(ks)^(m)C_(ds)C_(ys)A_(ds)A_(ds)A_(ds) 30 1042 ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds)G_(ks)T_(ks)T_(k) 1341951 N/A N/A 1280112816 AGGCUGTAAGAGTCAG A_(ks)G_(ks)G_(ks)^(m)C_(ds)U_(ys)G_(ds)T_(ds)A_(ds) 52 2844A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ks)A_(ks)G_(k) 1341955 N/A N/A12496 12511 AATTCACCTTGACTAA A_(ks)A_(ks)T_(ks)T_(ds)C_(ys)A_(ds)^(m)C_(ds) ^(m)C_(ds) 0 2144 T_(ds)T_(ds)G_(ds)A_(ds)^(m)C_(ds)T_(ks)A_(ks)A_(k)

TABLE 47Inhibition of HSD17B13 RNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound StartStop Start Stop Chemistry Notation % ID Number Site Site Site SiteSequence (5′ to 3′) (5′ to 3′) inhibition NO 1245927 N/A N/A 3433 3448AGTAGATGGTAAGTCA A_(ks)G_(ks)T_(ks)A_(ds)G_(ds)A_(ds)T_(ds)G_(ds)G_(ds)86 121 T_(ds)A_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1246023 N/A N/A5046 5061 GAGTGAATCATTCAGTG_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds)A_(ds)T_(ds) ^(m)C_(ds) 87 1526A_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)T_(k) 1341649 1314 1329 2112921144 CAGTCTTAAACCTTCC^(m)C_(ks)A_(ks)G_(ks)T_(ds)C_(ys)T_(ds)T_(ds)A_(ds)A_(ds) 59 30 A_(ds)^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(k) 1341652 1318 133321133 21148 TGAACAGTCTTAAACCT_(ks)G_(ks)A_(ks)A_(ds)C_(ys)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) 57 344T_(ds)T_(ds)A_(ds)A_(ds)A_(ks) ^(m)Ck^(m)C_(k) 1341655 1256 1271 2107121086 GCTTUTGTCCACCTTT G_(ks)^(m)C_(ks)T_(ks)T_(ds)U_(ys)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 75 2845^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)T_(ks)T_(k) 1341666 13091324 21124 21139 TTAAACCTTCCCTGTG T_(ks)T_(ks)A_(ks)A_(ds)A_(ys)^(m)C_(ds) ^(m)C_(ds)T_(ds) 23 2807 T_(ds) ^(m)C_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ds)G_(ks)T_(ks)G_(k) 1341669 1326 1341 21141 21156ATGCUACTTGAACAGT A_(ks)T_(ks)G_(ks) ^(m)G_(ds)U_(ys)A_(ds)^(m)C_(ds)T_(ds) 46 2846 T_(ds)G_(ds)A_(ds)A_(ds)^(m)C_(ds)A_(ks)G_(ks)T_(k) 1341671 1330 1345 21145 21160TGGAATGCTACTTGAA T_(ks)G_(ks)G_(ks)A_(ds)A_(ys)T_(ds)G_(ds)^(m)C_(ds)T_(ds) 79 2203 A_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ks)A_(ks)A_(k)1341673 1336 1351 21151 21166 ACAGATTGGAATGCTA A_(ks)^(m)C_(ks)A_(ks)G_(ds)A_(ys)T_(ds)T_(ds)G_(ds)G_(ds) 70 1668A_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ks)T_(ks)A_(k) 1341674 1322 1337 2113721152 TACTUGAACAGTCTTA T_(ks)A_(ks)^(m)C_(ks)T_(ds)U_(ys)G_(ds)A_(ds)A_(ds) 38 2847^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k) 1341686 13441359 21159 21174 GCATGGCTACAGATTG G_(ks)^(m)C_(ks)A_(ks)T_(ds)G_(ys)G_(ds) ^(m)C_(ds)T_(ds) 76 267 A_(ds)^(m)C_(ds)A_(ds)G_(ds)A_(ds)T_(ks)T_(ks)G_(k) 1341689 1354 1369 2116921184 ATATUCTGTGGCATGG A_(ks)T_(ks)A_(ks)T_(ds)U_(ys)^(m)C_(ds)T_(ds)G_(ds)T_(ds) 63 2848 G_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ks)G_(ks)G_(k) 1341693 1358 1373 21173 21188GTTGATATTCTGTGGC G_(ks)T_(ks)T_(ks)G_(ds)A_(ys)T_(ds)A_(ds)T_(ds)T_(ds)68 1280 ^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ks)G_(ks) ^(m)C_(k) 1341694 13491364 21164 21179 CTGTGGCATGGCTACA^(m)C_(ks)T_(ks)G_(ks)T_(ds)G_(ys)G_(ds) ^(m)C_(ds)A_(ds) 35 657T_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ds)A_(ks) ^(m)C_(ks)A_(k) 1341701 13891404 21204 21219 TCTCUTAGCTGTGCAC T_(ks) ^(m)C_(ks)T_(ks)^(m)C_(ds)U_(ys)T_(ds)A_(ds)G_(ds) 49 2849^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds) ^(m)C_(ks)A_(ks) ^(m)C_(k) 13417061367 1382 21182 21197 TGTGUTCTTGTTGATAT_(ks)G_(ks)T_(ks)G_(ds)U_(ys)T_(ds) ^(m)C_(ds)T_(ds)T_(ds) 41 2850G_(ds)T_(ds)T_(ds)G_(ds)A_(ks)T_(ks)A_(k) 1341707 698 713 12116 12131GAGACATGAGGTTTTG G_(ks)A_(ks)G_(ks)A_(ds)C_(ys)A_(ds)T_(ds)G_(ds)A_(ds)61 725 G_(ds)G_(ds)T_(ds)T_(ds)T_(ks)T_(ks)G_(k) 1341708 1395 1410 2121021225 ACTTGATCTCTTAGCT A_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ys)A_(ds)T_(ds)^(m)C_(ds) 39 813 T_(ds) ^(m)C_(ds)T_(ds)T_(ds)A_(ds)G_(ks)^(m)C_(ks)T_(k) 1341709 1418 1433 21233 21248 TTGAGATAAAGCTGCCT_(ks)T_(ks)G_(ks)A_(ds)G_(ys)A_(ds)T_(ds)A_(ds)A_(ds) 51 1670A_(ds)G_(ds) ^(m)C_(ds)T_(ds)G_(ks) ^(m)C_(ks) ^(m)C_(k) 1341717 14221437 21237 21252 CAGGUTGAGATAAAGC^(m)C_(ks)A_(ks)G_(ks)G_(ds)U_(ys)T_(ds)G_(ds)A_(ds) 55 2851G_(ds)A_(ds)T_(ds)A_(ds)A_(ds)A_(ks)G_(ks) ^(m)C_(k) 1341722 1466 148121281 21296 AGAGGCTAGGGAAATC A_(ks)G_(ks)A_(ks)G_(ds)G_(ys)^(m)C_(ds)T_(ds)A_(ds) 48 1048G_(ds)G_(ds)G_(ds)A_(ds)A_(ds)A_(ks)T_(ks) ^(m)C_(k) 1341723 1429 144421244 21259 ATATGTCCAGGTTGAG A_(ks)T_(ks)A_(ks)T_(ds)G_(ys)T_(ds)^(m)C_(ds) ^(m)C_(ds) 48 425A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)G_(ks)A_(ks)G_(k) 1341733 1491 1506 2130621321 ACCGUTTTGGGCTAAT A_(ks) ^(m)C_(ks)^(m)C_(ks)G_(ds)U_(ys)T_(ds)T_(ds)T_(ds) 65 2852 G_(ds)G_(ds)G_(ds)^(m)C_(ds)T_(ds)A_(ks)A_(ks)T_(k) 1341737 1495 1510 21310 21325TTGCACCGTTTTGGGC T_(ks)T_(ks)G_(ks) ^(m)C_(ds)A_(ys) ^(m)C_(ds)^(m)C_(ds)G_(ds) 50 1749 T_(ds)T_(ds)T_(ds)T_(ds)G_(ds)G_(ks)G_(ks)^(m)C_(k) 1341740 1499 1514 21314 21329 AGAGUTGCACCGTTTTA_(ks)G_(ks)A_(ks)G_(ds)U_(ys)T_(ds)G_(ds) ^(m)C_(ds) 68 2853 A_(ds)^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds)T_(ks)T_(ks)T_(k) 1341741 1624 163921439 21454 ATAGAGTCGGTCACCT A_(ks)T_(ks)A_(ks)G_(ds)A_(ys)G_(ds)T_(ds)^(m)C_(ds)G_(ds) 50 584 G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ks)^(m)C_(ks)T_(k) 1341742 1600 1615 21415 21430 GTATCTTATAAGACTAG_(ks)T_(ks)A_(ks)T_(ds)C_(ys)T_(ds)T_(ds)A_(ds)T_(ds) 79 1595A_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ks)T_(ks)A_(k) 1341751 1616 1631 2143121446 GGTCACCTTTCATAAT G_(ks)G_(ks)T_(ks) ^(m)C_(ds)A_(ys) ^(m)C_(ds)^(m)C_(ds)T_(ds) 48 1985 T_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ds)A_(ks)A_(ks)T_(k) 1341756 798 813 15679 15694TTCCATCTATCAGACT T_(ks)T_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ys)T_(ds)^(m)C_(ds)T_(ds) 38 571 A_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds)A_(ks)^(m)C_(ks)T_(k) 1341757 1620 1635 21435 21450 AGTCGGTCACCTTTCAA_(ks)G_(ks)T_(ks) ^(m)C_(ds)G_(ys)G_(ds)T_(ds) ^(m)C_(ds) 61 272 A_(ds)^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ks) ^(m)C_(ks)A_(k) 1341760 17121727 21527 21542 ACATCTCTGGGACCAA A_(ks)^(m)C_(ks)A_(ks)T_(ds)C_(ys)T_(ds) ^(m)C_(ds)T_(ds) 68 195G_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)A_(k) 1341765 16281643 21443 21458 TAAAATAGAGTCGGTCT_(ks)A_(ks)A_(ks)A_(ds)A_(ys)T_(ds)A_(ds)G_(ds)A_(ds) 52 895G_(ds)T_(ds) ^(m)C_(ds)G_(ds)G_(ks)T_(ks) ^(m)C_(k) 1341770 1721 173621536 21551 ATTGUCTAAACATCTC A_(ks)T_(ks)T_(ks)G_(ds)U_(ys)^(m)C_(ds)T_(ds)A_(ds)A_(ds) 73 2854 A_(ds) ^(m)C_(ds)A_(ds)T_(ds)^(m)C_(ks)T_(ks) ^(m)C_(k) 1341771 1716 1731 21531 21546CTAAACATCTCTGGGA ^(m)C_(ks)T_(ks)A_(ks)A_(ds)A_(ys)^(m)C_(ds)A_(ds)T_(ds) 32 2259 ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ks)G_(ks)A_(k) 1341776 1707 1722 21522 21537TCTGGGACCAAGGATA T_(ks) ^(m)C_(ks)T_(ks)G_(ds)G_(ys)G_(ds)A_(ds)^(m)C_(ds) 31 1830 ^(m)C_(ds)A_(ds)A_(ds)G_(ds)G_(ds)A_(ks)T_(ks)A_(k)1341779 1752 1767 21567 21582 TCCTGTGTTAGCTTTA T_(ks) ^(m)C_(ks)^(m)C_(ks)T_(ds)G_(ys)T_(ds)G_(ds)T_(ds) 72 1442 T_(ds)A_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ks)T_(ks)A_(k) 1341784 1771 1786 21586 21601TAGCCAGTACAGTTCC T_(ks)A_(ks)G_(ks)^(m)C_(ds)C_(ys)A_(ds)G_(ds)T_(ds)A_(ds) 70 1987^(m)C_(ds)A_(ds)G_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(k) 1341791 17841799 21599 21614 GTTTCTTATGTAATAGG_(ks)T_(ks)T_(ks)T_(ds)C_(ys)T_(ds)T_(ds)A_(ds)T_(ds) 25 897G_(ds)T_(ds)A_(ds)A_(ds)T_(ks)A_(ks)G_(k) 1341795 1776 1791 21591 21606TGTAATAGCCAGTACA T_(ks)G_(ks)T_(ks)A_(ds)A_(ys)T_(ds)A_(ds)G_(ds)^(m)C_(ds) 40 352 ^(m)C_(ds)A_(ds)G_(ds)T_(ds)A_(ks) ^(m)C_(ks)A_(k)1341797 1780 1795 21595 21610 CTTAUGTAATAGCCAG^(m)C_(ks)T_(ks)T_(ks)A_(ds)U_(ys)G_(ds)T_(ds)A_(ds)A_(ds) 75 2855T_(ds)A_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)G_(k) 1341799 2196 221122011 22026 GATTAGTCTTGATGTAG_(ks)A_(ks)T_(ks)T_(ds)A_(ys)G_(ds)T_(ds)mG_(ds)T_(ds) 45 1521T_(ds)G_(ds)A_(ds)T_(ds)G_(ks)T_(ks)A_(k) 1341804 2189 2204 22004 22019CTTGATGTAGTGGGAG^(m)G_(ks)T_(ks)T_(ks)G_(ds)A_(ys)T_(ds)G_(ds)T_(ds)A_(ds) 67 976G_(ds)T_(ds)G_(ds)G_(ds)G_(ks)A_(ks)G_(k) 1341808 2353 2368 22168 22183ATAACTACAAGAGGTT A_(ks)T_(ks)A_(ks)A_(ds)C_(ys)T_(ds)A_(ds)^(m)C_(ds)A_(ds) 61 1133 A_(ds)G_(ds)A_(ds)G_(ds)G_(ks)T_(ks)T_(k)1341813 2252 2267 22067 22082 AGAGGATAGTCCATGCA_(ks)G_(ks)A_(ks)G_(ds)G_(ys)A_(ds)T_(ds)A_(ds)G_(ds) 53 354 T_(ds)^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ks)G_(ks) ^(m)C_(k) 1341818 610 625 N/AN/A GAACAATATGGGATGA G_(ks)A_(ks)A_(ks)^(m)C_(ds)A_(ys)A_(ds)T_(ds)A_(ds)T_(ds) 50 1735G_(ds)G_(ds)G_(ds)A_(ds)T_(ks)G_(ks)A_(k) 1341823 N/A N/A 9516 9531ACACUAATATTGAGGC A_(ks) ^(m)C_(ks)A_(ks)^(m)C_(ds)U_(ys)A_(ds)A_(ds)T_(ds) 43 2856A_(ds)T_(ds)T_(ds)G_(ds)A_(ds)G_(ks)G_(ks) ^(m)C_(k) 1341824 810 82515691 15706 TATTGGTAAGTATTCCT_(ks)A_(ks)T_(ks)T_(ds)G_(ys)G_(ds)T_(ds)A_(ds)A_(ds) 41 1272G_(ds)T_(ds)A_(ds)T_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(k) 1341826 N/A N/A 93349349 CGATCCTATATACATC ^(m)C_(ks)G_(ks)A_(ks)T_(ds)C_(ys)^(m)C_(ds)T_(ds)A_(ds) 28 2788 T_(ds)A_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ks)T_(ks) ^(m)C_(k) 1341835 N/A N/A 9968 9983AGTAGTGTAAGCTGAG A_(ks)G_(ks)T_(ks)A_(ds)G_(ys)T_(ds)G_(ds)T_(ds)A_(ds)68 2155 A_(ds)G_(ds) ^(m)C_(ds)T_(ds)G_(ks)A_(ks)G_(k) 1341837 N/A N/A9603 9618 CACAUATGTGAAGAGC ^(m)CkSA_(ks)^(m)C_(ks)A_(ds)U_(ys)A_(ds)T_(ds)G_(ds) 65 2857T_(ds)G_(ds)A_(ds)A_(ds)G_(ds)A_(ks)G_(ks) ^(m)C_(k) 1341843 N/A N/A11568 11583 TGACAATGGTTGATAG T_(ks)G_(ks)A_(ks)^(m)C_(ds)A_(ys)A_(ds)T_(ds)G_(ds)G_(ds) 42 1700T_(ds)T_(ds)G_(ds)A_(ds)T_(ks)A_(ks)G_(k) 1341844 N/A N/A 11853 11868AGCAGAATTGTGAACG A_(ks)G_(ks)^(m)C_(ks)A_(ds)G_(ys)A_(ds)A_(ds)T_(ds)T_(ds) 51 844G_(ds)T_(ds)G_(ds)A_(ds)A_(ks) ^(m)C_(ks)G_(k) 1341848 N/A N/A 1242112436 TGGTAACGGTGATCAA T_(ks)G_(ks)G_(ks)T_(ds)A_(ys)A_(ds)^(m)C_(ds)G_(ds)G_(ds) 41 67 T_(ds)G_(ds)A_(ds)T_(ds)^(m)C_(ks)A_(ks)A_(k) 1341854 N/A N/A 14199 14214 TATTATGTGATTGAGTT_(ks)A_(ks)T_(ks)T_(ds)A_(ys)T_(ds)G_(ds)T_(ds)G_(ds) 28 73A_(ds)T_(ds)T_(ds)G_(ds)A_(ks)G_(ks)T_(k) 1341858 N/A N/A 14918 14933TAATACATTAGCAAGC T_(ks)A_(ks)A_(ks)T_(ds)A_(ys)^(m)C_(ds)A_(ds)T_(ds)T_(ds) 26 2266 A_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ks)G_(ks) ^(m)C_(k) 1341865 1019 1034 20834 20849TGCAGCATTGATTCGA T_(ks)G_(ks) ^(m)C_(ks)A_(ds)G_(ys) ^(m)C_(ds)A_(ds) 65419 T_(ds)T_(ds)G_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ks)G_(ks)A_(k) 1341866N/A N/A 15498 15513 TGCTGCATTAATGCCA T_(ks)G_(ks) ^(m)C_(ks)T_(ds)G_(ys)^(m)C_(ds)A_(ds)T_(ds) 32 2485 T_(ds)A_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ks)^(m)C_(ks)A_(k) 1341869 N/A N/A 16129 16144 TCCAUAATAATAGCTC T_(ks)^(m)C_(ks) ^(m)C_(ks)A_(ds)U_(ys)A_(ds)A_(ds)T_(ds) 58 2858A_(ds)A_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k) 1341872 N/AN/A 16292 16307 TTAGUTAGAATAGTCTT_(ks)T_(ks)A_(ks)G_(ds)U_(ys)T_(ds)A_(ds)G_(ds)A_(ds) 35 2859A_(ds)T_(ds)A_(ds)GdST_(ks) ^(m)C_(ks)T_(k) 1341875 N/A N/A 16223 16238CTTTUTATAGACTGGG^(m)C_(ks)T_(ks)T_(ks)T_(ds)U_(ys)T_(ds)A_(ds)T_(ds)A_(ds) 34 2860G_(ds)A_(ds) ^(m)C_(ds)T_(ds)G_(ks)G_(ks)G_(k) 1341879 N/A N/A 1799018005 TTAGUATAGTTATCTTT_(ks)T_(ks)A_(ks)G_(ds)U_(ys)A_(ds)T_(ds)A_(ds)G_(ds) 22 2861T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(ks)T_(k) 1341881 N/A N/A 1799518010 TGAAGTTAGTATAGTTT_(ks)G_(ks)A_(ks)A_(ds)G_(ys)T_(ds)T_(ds)A_(ds)G_(ds) 62 1405T_(ds)A_(ds)T_(ds)A_(ds)G_(ks)T_(ks)T_(k) 1341884 N/A N/A 16384 16399AATCCCAACCAAACTT A_(ks)A_(ks)T_(ks)m_(ds)C_(ys)m_(ds)A_(ds)A_(ds) 7 2755^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ks)T_(ks)T_(k) 1341888N/A N/A 18095 18110 AATTGATACACCAATGA_(ks)A_(ks)T_(ks)T_(ds)G_(ys)A_(ds)T_(ds)A_(ds) ^(m)C_(ds) 40 2525A_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ks)T_(ks)G_(k) 1341897 1084 109920899 20914 CTGCUGCTAGTGCCAA ^(m)C_(ks)T_(ks)G_(ks)^(m)C_(ds)U_(ys)G_(ds) ^(m)C_(ds)T_(ds) 66 2862 A_(ds)G_(ds)T_(ds)G_(ds)^(m)C_(ds) ^(m)C_(ks)A_(ks)A_(k) 1341902 N/A N/A 19913 19928GTGCATCTTAAGATAC G_(ks)T_(ks)G_(ks) ^(m)C_(ds)A_(ys)T_(ds)^(m)C_(ds)T_(ds) 40 2806 T_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ks)A_(ks)^(m)C_(k) 1341906 N/A N/A 18693 18708 AGACUTTGAGACTCTTA_(ks)G_(ks)A_(ks) ^(m)C_(ds)U_(ys)T_(ds)T_(ds)G_(ds)A_(ds) 48 2863G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(ks)T_(k) 1341909 N/A N/A19909 19924 ATCTUAAGATACCCAG A_(ks)T_(ks)^(m)C_(ks)T_(ds)U_(ys)A_(ds)A_(ds)G_(ds)A_(ds) 55 2864 T_(ds)A_(ds)^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)G_(k) 1341911 1080 1095 2089520910 TGCTAGTGCCAAACCA T_(ks)G_(ks)^(m)C_(ks)T_(ds)A_(ys)G_(ds)T_(ds)G_(ds) 80 1432 ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(k) 1341912 N/A N/A19905 19920 TAAGATACCCAGGTTG T_(ks)A_(ks)A_(ks)G_(ds)A_(ys)T_(ds)A_(ds)^(m)C_(ds) 11 2790 ^(m)C_(ds)^(m)C_(ds)A_(ds)G_(ds)G_(ds)T_(ks)T_(ks)G_(k) 1341922 N/A N/A 2011420129 GCATCAAGACATTCTA G_(ks)^(m)C_(ks)A_(ks)T_(ds)C_(ys)A_(ds)A_(ds)G_(ds) 51 1565 A _(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ks)T_(ks)A_(k) 1341926 N/A N/A 1999920014 CAGTUTTCCTCATGAT ^(m)C_(ks)A_(ks)G_(ks)T_(ds)U_(ys)T_(ds)T_(ds)^(m)C_(ds) 0 2865 ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ks)A_(ks)T_(k) 1341932 1076 1091 20891 20906AGTGCCAAACCAATGT A_(ks)G_(ks)T_(ks)G_(ds)C_(ys)C_(ds)A_(ds)A_(ds) 241120 A_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ks)G_(ks)T_(k) 1341933N/A N/A 20388 20403 CTATAGTAATCACAAG^(m)C_(ks)T_(ks)A_(ks)T_(ds)A_(ys)G_(ds)T_(ds)A_(ds)A_(ds) 37 1644T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ks)A_(ks)G_(k) 1341935 N/A N/A20190 20205 AGTTATTAGAAGTCAGA_(ks)G_(ks)T_(ks)T_(ds)A_(ys)T_(ds)T_(ds)A_(ds)G_(ds) 25 2746A_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ks)A_(ks)G_(k) 1341938 N/A N/A 2037820393 CACAAGTAAGGTAAAG ^(m)C_(ks)A_(ks)^(m)C_(ks)A_(ds)A_(ys)G_(ds)T_(ds)A_(ds) 43 2448A_(ds)G_(ds)G_(ds)T_(ds)A_(ds)A_(ks)A_(ks)G_(k) 1341944 N/A N/A 2048420499 CTTCATAGTGGACTTC ^(m)C_(ks)T_(ks)T_(ks)^(m)C_(ds)A_(ys)T_(ds)A_(ds)G_(ds) 35 711 T_(ds)G_(ds)G_(ds)A_(ds)^(m)C_(ds)T_(ks)T_(ks) ^(m)C_(k) 1341952 N/A N/A 12804 12819CTCAGGCTGTAAGAGT ^(m)C_(ks)T_(ks) ^(m)C_(ks)A_(ds)G_(ys)G_(ds)^(m)C_(ds)T_(ds) 46 2240 G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)A_(ks)G_(ks)T_(k)1341956 N/A N/A 12499 12514 AGAAATTCACCTTGACA_(ks)G_(ks)A_(ks)A_(ds)A_(ys)T_(ds)T_(ds) ^(m)C_(ds)A_(ds) 9 2284^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ks)A_(ks) ^(m)C_(k)

TABLE 48Inhibition of HSD17B13 RNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 Compound Start StopStart Stop Chemistry Notation % SEQ Number Site Site Site SiteSequence (5′ to 3′) (5′ to 3′) inhibition ID NO 1245927 N/A N/A 34333448 AGTAGATGGTAAGTCAA_(ks)G_(ks)T_(ks)A_(ds)G_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 82 121T_(ds)A_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1246023 N/A N/A 5046 5061GAGTGAATCATTCAGT G_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds)A_(ds)T_(ds)^(m)C_(ds) 86 1526 A_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)T_(k)1341651 1315 1330 21130 21145 ACAGUCTTAAACCTTC A_(ks)^(m)C_(ks)A_(ks)G_(ds)U_(ys) ^(m)C_(ds)T_(ds)T_(ds) 81 2866A_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)T_(ks) ^(m)C_(k) 13416561257 1272 21072 21087 AGCTUTTGTCCACCTT A_(ks)G_(ks)^(m)C_(ks)T_(ds)U_(ys)T_(ds)T_(ds)G_(ds)T_(ds) 72 2867 ^(m)C_(ds)^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks)T_(k) 1341657 613 628 N/AN/A CTGGAACAATATGGGA ^(m)C_(ks)T_(ks)G_(ks)G_(ds)A_(ys)A_(ds)^(m)C_(ds)A_(ds) 45 1969 A_(ds)T_(ds)A_(ds)T_(ds)G_(ds)G_(ds)G_(ks)A_(k)1341659 1327 1342 21142 21157 AATGCTACTTGAACAGA_(ks)A_(ks)T_(ks)G_(ds)C_(ys)T_(ds)A_(ds) ^(m)C_(ds)T_(ds) 34 1045T_(ds)G_(ds)A_(ds)A_(ds) ^(m)C_(ks)A_(ks)G_(k) 1341662 1319 1334 2113421149 TTGAACAGTCTTAAAC T_(ks)T_(ks)G_(ks)A_(ds)A_(ys)^(m)C_(ds)A_(ds)G_(ds)T_(ds) 11 422^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ks)A_(ks) ^(m)C_(k) 1341665 1310 132521125 21140 CTTAAACCTTCCCTGT ^(m)C_(ks)T_(ks)T_(ks)A_(ds)A_(ys)A_(ds)^(m)C_(ds) ^(m)C_(ds) 24 1823 T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ks)G_(ks)T_(k) 1341675 1323 1338 21138 21153CTACUTGAACAGTCTT ^(m)C_(ks)T_(ks)A_(ks)^(m)C_(ds)U_(ys)T_(ds)G_(ds)A_(ds) 79 2868 A_(ds)^(m)C_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ks)T_(ks)T_(k) 1341679 1355 137021170 21185 GATAUTCTGTGGCATG GsA_(ks)T_(ks)A_(ds)U_(ys)T_(ds)^(m)C_(ds)T_(ds)G_(ds) 60 2869 T_(ds)G_(ds)G_(ds)^(m)C_(ds)A_(ks)T_(ks)G_(k) 1341681 1337 1352 21152 21167TACAGATTGGAATGCT T_(ks)A_(ks)^(m)C_(ks)A_(ds)G_(ys)A_(ds)T_(ds)T_(ds)G_(ds) 60 1746G_(ds)A_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)T_(k) 1341682 700 715 1211812133 CAGAGACATGAGGTTT ^(m)C_(ks)A_(ks)G_(ks)A_(ds)G_(ys)A_(ds)^(m)C_(ds)A_(ds) 61 2319 T_(ds)G_(ds)A_(ds)G_(ds)G_(ds)T_(ks)T_(ks)T_(k)1341684 1331 1346 21146 21161 TTGGAATGCTACTTGAT_(ks)T_(ks)G_(ks)G_(ds)A_(ys)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) 65 1279T_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ks)G_(ks)A_(k) 1341687 1346 1361 2116121176 TGGCATGGCTACAGAT T_(ks)G_(ks)G_(ks)^(m)C_(ds)A_(ys)T_(ds)G_(ds)G_(ds) 57 423 ^(m)C_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds)G_(ks)A_(ks)T_(k) 1341688 1359 1374 21174 21189TGTTGATATTCTGTGG T_(ks)G_(ks)T_(ks)T_(ds)G_(ys)A_(ds)T_(ds)A_(ds)T_(ds)48 1358 T_(ds) ^(m)C_(ds)T_(ds)G_(ds)TkSG_(ks)G_(k) 1341695 1351 136621166 21181 TTCTGTGGCATGGCTA T_(ks)T_(ks)^(m)C_(ks)T_(ds)G_(ys)T_(ds)G_(ds)G_(ds) ^(m)C_(ds) 65 812A_(ds)T_(ds)G_(ds)G_(ds)mG_(ks)T_(ks)A_(k) 1341700 1384 1399 21199 21214TAGCUGTGCACTCATT T_(ks)A_(ks)G_(ks) ^(m)C_(ds)U_(ys)G_(ds)T_(ds)G_(ds)60 2870 ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ks)T_(ks)T_(k)1341704 1391 1406 21206 21221 GATCUCTTAGCTGTGC G_(ks)A_(ks)T_(ks)^(m)C_(ds)U_(ys) ^(m)C_(ds)T_(ds)T_(ds) 65 2871 A_(ds)G_(ds)^(m)C_(ds)T_(ds)G_(ds)T_(ks)G_(ks) ^(m)C_(k) 1341710 1419 1434 2123421249 GTTGAGATAAAGCTGCG_(ks)T_(ks)T_(ks)G_(ds)A_(ys)G_(ds)A_(ds)T_(ds)A_(ds) 51 1748A_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)G_(ks) ^(m)C_(k) 1341712 1423 143821238 21253 CCAGGTTGAGATAAAG ^(m)C_(ks)^(m)C_(ks)A_(ks)G_(ds)G_(ys)T_(ds)T_(ds)G_(ds) 49 33A_(ds)G_(ds)A_(ds)T_(ds)A_(ds)A_(ks)A_(ks)G_(k) 1341715 1398 1413 2121321228 GAAACTTGATCTCTTAG_(ks)A_(ks)A_(ks)A_(ds)C_(ys)T_(ds)T_(ds)G_(ds)A_(ds) 59 2717 T_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ks)T_(ks)A_(k) 1341720 1496 1511 2131121326 GTTGCACCGTTTTGGG G_(ks)T_(ks)T_(ks)G_(ds)C_(ys)A_(ds) ^(m)C_(ds)^(m)C_(ds) 38 1827 G_(ds)T_(ds)T_(ds)T_(ds)T_(ds)G_(ks)G_(ks)G_(k)1341724 1431 1446 21246 21261 AAATATGTCCAGGTTGA_(ks)A_(ks)A_(ks)T_(ds)A_(ys)T_(ds)G_(ds)T_(ds) ^(m)C_(ds) 63 581^(m)C_(ds)A_(ds)G_(ds)G_(ds)T_(ks)T_(ks)G_(k) 1341730 1488 1503 2130321318 GTTTUGGGCTAATGAA G_(ks)T_(ks)T_(ks)T_(ds)U_(ys)G_(ds)G_(ds)G_(ds)^(m)C_(ds) 30 2872 T_(ds)A_(ds)A_(ds)T_(ds)G_(ks)A_(ks)A_(k) 1341732 801816 15682 15697 GTATUCCATCTATCAG G_(ks)T_(ks)A_(ks)T_(ds)U_(ys)^(m)C_(ds) ^(m)C_(ds)A_(ds) 41 2873 T_(ds) ^(m)C_(ds)T_(ds)A_(ds)T_(ds)^(m)C_(ks)A_(ks)G_(k) 1341735 1492 1507 21307 21322 CACCGTTTTGGGCTAA^(m)C_(ks)A_(ks) ^(m)Cks^(m)C_(ds)G_(ys)T_(ds)T_(ds)T_(ds) 82 1516T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ks)A_(ks)A_(k) 1341746 1501 151621316 21331 ATAGAGTTGCACCGTTA_(ks)T_(ks)A_(ks)G_(ds)A_(ys)G_(ds)T_(ds)T_(ds)G_(ds) 59 192^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)G_(ks)T_(ks)T_(k) 1341747 16021617 21417 21432 ATGTATCTTATAAGAC A_(ks)T_(ks)G_(ks)T_(ds)A_(ys)T_(ds)^(m)C_(ds)T_(ds)T_(ds) 3 1751 A_(ds)T_(ds)A_(ds)A_(ds)G_(ks)A_(ks)^(m)C_(k) 1341749 1621 1636 21436 21451 GAGTCGGTCACCTTTCG_(ks)A_(ks)G_(ks)T_(ds)C_(ys)G_(ds)G_(ds)T_(ds) ^(m)C_(ds) 55 350A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ks)T_(ks) ^(m)C_(k) 1341750 16251640 21440 21455 AATAGAGTCGGTCACCA_(ks)A_(ks)T_(ks)A_(ds)G_(ys)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) 57 662G_(ds)G_(ds)T_(ds) ^(m)C_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(k) 1341752 16171632 21432 21447 CGGTCACCTTTCATAA^(m)C_(ks)G_(ks)G_(ks)T_(ds)C_(ys)A_(ds) ^(m)C_(ds) ^(m)C_(ds) 42 36T_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ks)A_(ks)A_(k) 1341762 1713 172821528 21543 AACAUCTCTGGGACCA A_(ks)A_(ks) ^(m)C_(ks)A_(ds)U_(ys)^(m)C_(ds)T_(ds) ^(m)C_(ds) 64 2874 T_(ds)G_(ds)G_(ds)G_(ds)A_(ds)^(m)C_(ks) ^(m)C_(ks)A_(k) 1341766 1629 1644 21444 21459TTAAAATAGAGTCGGT T_(ks)T_(ks)A_(ks)A_(ds)A_(ys)A_(ds)T_(ds)A_(ds)G_(ds)70 973 A_(ds)G_(ds)T_(ds) ^(m)C_(ds)G_(ks)G_(ks)T_(k) 1341769 1726 174121541 21556 CTAAAATTGTCTAAAC^(m)C_(ks)T_(ks)A_(ks)A_(ds)A_(ys)A_(ds)T_(ds)T_(ds)G_(ds) 13 2590T_(ds) ^(m)C_(ds)T_(ds)A_(ds)A_(ks)A_(ks) ^(m)C_(k) 1341772 1717 173221532 21547 TCTAAACATCTCTGGG T_(ks) ^(m)C_(ks)T_(ks)A_(ds)A_(ys)A_(ds)^(m)C_(ds)A_(ds) 36 2287 T_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ds)T_(ds)G_(ks)G_(ks)G_(k) 1341775 1708 1723 21523 21538CTCTGGGACCAAGGAT ^(m)C_(ks)T_(ks)^(m)C_(ks)T_(ds)G_(ys)G_(ds)G_(ds)A_(ds) 43 1908 ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds)G_(ds)G_(ks)A_(ks)T_(k) 1341778 1773 1788 2158821603 AATAGCCAGTACAGTT A_(ks)A_(ks)T_(ks)A_(ds)G_(ys) ^(m)C_(ds)^(m)C_(ds)A_(ds) 66 118 G_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds)G_(ks)T_(ks)T_(k) 1341782 1766 1781 21581 21596AGTACAGTTCCTTTTC A_(ks)G_(ks)T_(ks)A_(ds)C_(ys)A_(ds)G_(ds)T_(ds)T_(ds)56 1597 ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ks)T_(ks) ^(m)C_(k) 1341790791 806 15672 15687 TATCAGACTTCTTACG T_(ks)A_(ks)T_(ks)^(m)C_(ds)A_(ys)G_(ds)A_(ds) ^(m)C_(ds) 27 103 T_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ks) ^(m)C_(ks)G_(k) 1341794 1777 1792 2159221607 ATGTAATAGCCAGTACA_(ks)T_(ks)G_(ks)T_(ds)A_(ys)A_(ds)T_(ds)A_(ds)G_(ds) 42 430 ^(m)C_(ds)^(m)C_(ds)A_(ds)G_(ds)T_(ks)A_(ks) ^(m)C_(k) 1341798 1781 1796 2159621611 TCTTATGTAATAGCCA T_(ks)^(m)C_(ks)T_(ks)T_(ds)A_(ys)T_(ds)G_(ds)T_(ds)A_(ds) 64 742A_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(k) 1341802 2191 220622006 22021 GTCTUGATGTAGTGGG G_(ks)T_(ks)^(m)C_(ks)T_(ds)U_(ys)G_(ds)A_(ds)T_(ds)G_(ds) 63 2875T_(ds)A_(ds)G_(ds)T_(ds)G_(ks)G_(ks)G_(k) 1341803 2184 2199 21999 22014TGTAGTGGGAGTCGGA T_(ks)G_(ks)T_(ks)A_(ds)G_(ys)T_(ds)G_(ds)G_(ds)G_(ds)50 587 A_(ds)G_(ds)T_(ds) ^(m)C_(ds)G_(ks)G_(ks)A_(k) 1341811 2355 237022170 22185 TTATAACTACAAGAGG T_(ks)T_(ks)A_(ks)T_(ds)A_(ys)A_(ds)^(m)C_(ds)T_(ds)A_(ds) 58 1289^(m)C_(ds)A_(ds)A_(ds)G_(ds)A_(ks)G_(ks)G_(k) 1341812 812 827 1569315708 CTTAUTGGTAAGTATT^(m)C_(ks)T_(ks)T_(ks)A_(ds)U_(ys)T_(ds)G_(ds)G_(ds)T_(ds) 0 2876A_(ds)A_(ds)G_(ds)T_(ds)A_(ks)T_(ks)T_(k) 1341814 2254 2269 22069 22084CAAGAGGATAGTCCAT^(m)C_(ks)A_(ks)A_(ks)G_(ds)A_(ys)G_(ds)G_(ds)A_(ds)T_(ds) 60 510A_(ds)G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)T_(k) 1341815 2245 226022060 22075 AGTCCATGCAAAAGCA A_(ks)G_(ks)T_(ks)^(m)C_(ds)C_(ys)A_(ds)T_(ds)G_(ds) 73 120^(m)C_(ds)A_(ds)A_(ds)A_(ds)A_(ds)G_(ks) ^(m)C_(ks)A_(k) 1341819 N/A N/A9337 9352 CCTCGATCCTATATAC ^(m)C_(ks) ^(m)C_(ks)T_(ks)^(m)C_(ds)G_(ys)A_(ds)T_(ds) ^(m)C_(ds) 9 2812mC_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ks)A_(ks) ^(m)C_(k) 1341821 N/A N/A9518 9533 CTACACTAATATTGAG ^(m)C_(ks)T_(ks)A_(ks) ^(m)C_(ds)A_(ys)^(m)C_(ds)T_(ds)A_(ds) 29 59A_(ds)T_(ds)A_(ds)T_(ds)T_(ds)G_(ks)A_(ks)G_(k) 1341829 N/A N/A 99619976 TAAGCTGAGAGTTCTAT_(ks)A_(ks)A_(ks)G_(ds)C_(ys)T_(ds)G_(ds)A_(ds)G_(ds) 27 2499A_(ds)G_(ds)T_(ds)T_(ds) ^(m)C_(ks)T_(ks)A_(k) 1341834 N/A N/A 9971 9986TTGAGTAGTGTAAGCT T_(ks)T_(ks)G_(ks)A_(ds)G_(ys)T_(ds)A_(ds)G_(ds)T_(ds)35 2346 G_(ds)T_(ds)A_(ds)A_(ds)G_(ks) ^(m)C_(ks)T_(k) 1341838 1022 103720837 20852 CTTTGCAGCATTGATT ^(m)C_(ks)T_(ks)T_(ks)T_(ds)G_(ys)^(m)C_(ds)A_(ds)G_(ds) 19 2463^(m)C_(ds)A_(ds)T_(ds)T_(ds)G_(ds)A_(ks)T_(ks)T_(k) 1341841 N/A N/A11571 11586 TCTTGACAATGGTTGA T_(ks) ^(m)C_(ks)T_(ks)T_(ds)G_(ys)A_(ds)^(m)C_(ds)A_(ds) 56 2440 A_(ds)T_(ds)G_(ds)G_(ds)T_(ds)T_(ks)G_(ks)A_(k)1341846 N/A N/A 11855 11870 TAAGCAGAATTGTGAAT_(ks)A_(ks)A_(ks)G_(ds)C_(ys)A_(ds)G_(ds)A_(ds)A_(ds) 26 2361T_(ds)T_(ds)G_(ds)T_(ds)G_(ks)A_(ks)A_(k) 1341849 N/A N/A 14194 14209TGTGATTGAGTTCTCC T_(ks)G_(ks)T_(ks)G_(ds)A_(ys)T_(ds)T_(ds)G_(ds)A_(ds)34 2020 G_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks) ^(m)C_(k) 1341852N/A N/A 12423 12438 GGTGGTAACGGTGATCG_(ks)G_(ks)T_(ks)G_(ds)G_(ys)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) 35 2591G_(ds)G_(ds)T_(ds)G_(ds)A_(ks)T_(ks) ^(m)C_(k) 1341857 N/A N/A 1420414219 CAGAUTATTATGTGAT^(m)C_(ks)A_(ks)G_(ks)A_(ds)U_(ys)T_(ds)A_(ds)T_(ds)T_(ds) 32 2877A_(ds)T_(ds)G_(ds)T_(ds)G_(ks)A_(ks)T_(k) 1341859 N/A N/A 15491 15506TTAAUGCCACCCTACC T_(ks)T_(ks)A_(ks)A_(ds)U_(ys)G_(ds) ^(m)C_(ds)^(m)C_(ds) 8 2878 A_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)A_(ks)^(m)C_(ks) ^(m)C_(k) 1341868 N/A N/A 16282 16297 TAGTCTTCAGCAAAGTT_(ks)A_(ks)G_(ks)T_(ds)C_(ys)T_(ds)T_(ds) ^(m)C_(ds)A_(ds) 41 2632G_(ds) ^(m)C_(ds)A_(ds)AdSA_(ks)G_(ks)T_(k) 1341874 N/A N/A 16131 16146GCTCCATAATAATAGC G_(ks) ^(m)C_(ks)T_(ks)^(m)C_(ds)C_(ys)A_(ds)T_(ds)A_(ds) 16 2665A_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ks)G_(ks) ^(m)C_(k) 1341880 N/A N/A17991 18006 GTTAGTATAGTTATCTG_(ks)T_(ks)T_(ks)A_(ds)G_(ys)T_(ds)A_(ds)T_(ds)A_(ds) 52 1171G_(ds)T_(ds)T_(ds)A_(ds)T_(ks) ^(m)C_(ks)T_(k) 1341883 N/A N/A 1799618011 ATGAAGTTAGTATAGTA_(ks)T_(ks)G_(ks)A_(ds)A_(ys)G_(ds)T_(ds)T_(ds)A_(ds) 38 1483G_(ds)T_(ds)A_(ds)T_(ds)A_(ks)G_(ks)T_(k) 1341886 N/A N/A 16377 16392ACCAAACTTCCAGCAG A_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)A_(ys)A_(ds)^(m)C_(ds)T_(ds) 54 1948 T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)G_(ds)^(m)C_(ks)A_(ks)G_(k) 1341891 N/A N/A 18097 18112 GAAAUTGATACACCAAG_(ks)A_(ks)A_(ks)A_(ds)U_(ys)T_(ds)G_(ds)A_(ds)T_(ds) 58 2879 A_(ds)^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)A_(k) 1341894 N/A N/A 1798618001 TATAGTTATCTTCTCAT_(ks)A_(ks)T_(ks)A_(ds)G_(ys)T_(ds)T_(ds)A_(ds)T_(ds) 33 2295^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(ks)A_(k) 1341899 N/A N/A18695 18710 AAAGACTTTGAGACTC A_(ks)A_(ks)A_(ks)G_(ds)A_(ys)^(m)C_(ds)T_(ds)T_(ds)T_(ds) 76 1250 G_(ds)A_(ds)G_(ds)A_(ds)^(m)C_(ks)T_(ks) ^(m)C_(k) 1341901 N/A N/A 19914 19929 AGTGCATCTTAAGATAA_(ks)G_(ks)T_(ks)G_(ds)C_(ys)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) 17 2130T_(ds)A_(ds)A_(ds)G_(ds)A_(ks)T_(ks)A_(k) 1341904 1081 1096 20896 20911CTGCUAGTGCCAAACC ^(m)C_(ks)T_(ks)G_(ks)^(m)C_(ds)U_(ys)A_(ds)G_(ds)T_(ds) 67 2880 G_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(k) 1341915 N/A N/A 1990619921 TTAAGATACCCAGGTT T_(ks)T_(ks)A_(ks)A_(ds)G_(ys)A_(ds)T_(ds)A_(ds)^(m)C_(ds) 30 163 ^(m)C_(ds) ^(m)C_(ds)A_(ds)G_(ds)G_(ks)T_(ks)T_(k)1341917 N/A N/A 19910 19925 CATCUTAAGATACCCA ^(m)C_(ks)A_(ks)T_(ks)^(m)C_(ds)U_(ys)T_(ds)A_(ds)A_(ds) 56 2881 G_(ds)A_(ds)T_(ds)A_(ds)^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(k) 1341921 N/A N/A 20116 20131CAGCATCAAGACATTC ^(m)C_(ks)A_(ks)G_(ks) ^(m)C_(ds)A_(ys)T_(ds)^(m)C_(ds)A_(ds) 52 2191 A_(ds)G_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ks)T_(ks)^(m)C_(k) 1341925 N/A N/A 20009 20024 AGAGAGTAATCAGTTTA_(ks)G_(ks)A_(ks)G_(ds)A_(ys)G_(ds)T_(ds)A_(ds)A_(ds) 25 2651 T_(ds)^(m)C_(ds)A_(ds)G_(ds)T_(ks)T_(ks)T_(k) 1341934 N/A N/A 20192 20207GCAGUTATTAGAAGTC G_(ks)^(m)C_(ks)A_(ks)G_(ds)U_(ys)T_(ds)A_(ds)T_(ds)T_(ds) 59 2882A_(ds)G_(ds)A_(ds)A_(ds)G_(ks)T_(ks) ^(m)C_(k) 1341937 1077 1092 2089220907 TAGTGCCAAACCAATG T_(ks)A_(ks)G_(ks)T_(ds)G_(ys) ^(m)C_(ds)^(m)C_(ds)A_(ds) 55 1198 A_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ks)T_(ks)G_(k) 1341939 1085 1100 20900 20915ACTGCTGCTAGTGCCA A_(ks) ^(m)C_(ks)T_(ks)G_(ds)C_(ys)T_(ds)G_(ds)^(m)C_(ds) 64 1821 T_(ds)A_(ds)G_(ds)T_(ds)G_(ds) ^(m)C_(ks)^(m)C_(ks)A_(k) 1341943 N/A N/A 20486 20501 AACTUCATAGTGGACTA_(ks)A_(ks) ^(m)C_(ks)T_(ds)U_(ys) ^(m)C_(ds)A_(ds)T_(ds) 38 2883A_(ds)G_(ds)T_(ds)G_(ds)G_(ds)A_(ks) ^(m)C_(ks)T_(k) 1341945 N/A N/A20422 20437 ACAGUAAAATTATGCC A_(ks)^(m)C_(ks)A_(ks)G_(ds)U_(ys)A_(ds)A_(ds)A_(ds) 24 2884A_(ds)T_(ds)T_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks) ^(m)C_(k) 1341947 N/AN/A 20381 20396 AATCACAAGTAAGGTA A_(ks)A_(ks)T_(ks)^(m)C_(ds)A_(ys)mC_(ds)A_(ds)A_(ds) 31 1333G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ks)T_(ks)A_(k) 1341954 N/A N/A 1250112516 GCAGAAATTCACCTTG G_(ks)^(m)C_(ks)A_(ks)G_(ds)A_(ys)A_(ds)A_(ds)T_(ds)T_(ds) 54 1002^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)T_(ks)G_(k)

TABLE 49Inhibition of HSD17B13 RNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 SEQ Compound StartStop Start Stop Sequence Chemistry Notation % ID Number Site Site SiteSite (5′ to 3′) (5′ to 3′) inhibition NO 1245927 N/A N/A 3433 3448AGTAGATGGTAAGTCA A_(ks)G_(ks)T_(ks)A_(ds)G_(ds)A_(ds)T_(ds)G_(ds)G_(ds)86 121 T_(ds)A_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1246023 N/A N/A5046 5061 GAGTGAATCATTCAGTG_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds)A_(ds)T_(ds) ^(m)C_(ds) 82 1526A_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks)T_(k) 1341508 N/A N/A 1418914204 TTGAGTTCTCCACTGC T_(ks)T_(ks)G_(ks)A_(ds)G_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ds) 26 2885 ^(m)C_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ks)T_(ks)G_(ks) ^(m)C_(e) 1341518 1251 1266 21066 21081TGTCCACCTTTAAATG T_(ks)G_(ks)T_(ks) ^(m)C_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds) ^(m)C_(ds)T_(ds) 28 1666T_(ds)T_(ds)A_(ds)A_(ks)A_(ks)T_(k)gG_(e) 1341519 1310 1325 21125 21140CTTAAACCTTCCCTGT ^(m)C_(ks)T_(ks)T_(ks)A_(ds)A_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds) 34 1823 T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)^(m)C_(ks)T_(ks)G_(ks)T_(e) 1341520 1328 1343 21143 21158GAATGCTACTTGAACA G_(ks)A_(ks)A_(ks)T_(ds)G_(ds) ^(m)C_(dS)T_(ds)A_(ds)56 1123 ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ks)A_(ks) ^(m)C_(ks)A_(e) 13415211330 1345 21145 21160 TGGAATGCTACTTGAAT_(ks)G_(ks)G_(ks)A_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds) 57 2203A_(ds) ^(m)C_(ds)T_(ds)T_(ks)G_(ks)A_(ks)A_(e) 1341522 1320 1335 2113521150 CTTGAACAGTCTTAAA ^(m)C_(ks)T_(ks)T_(ks)G_(ds)A_(ds)A_(ds)^(m)C_(ds)A_(ds) 43 500 G_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ks)A_(ks)A_(ks)A_(e) 1341523 1309 1324 21124 21139TTAAACCTTCCCTGTG T_(ks)T_(ks)A_(ks)A_(dS)A_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ds) 18 2807 T_(ds) ^(m)C_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ks)G_(ks)T_(ks)G_(e) 1341524 1319 1334 21134 21149TTGAACAGTCTTAAAC T_(ks)T_(ks)G_(ks)A_(ds)A_(ds)^(m)C_(ds)A_(ds)G_(ds)T_(ds) 35 422^(m)C_(ds)T_(ds)T_(ds)A_(ks)A_(ks)A_(ks) ^(m)C_(e) 1341525 1264 127921079 21094 GGGAGGTAGCTTTTGTG_(ks)G_(ks)G_(ks)A_(ds)G_(ds)G_(ds)T_(ds)A_(dS)G_(ds) 40 343^(m)C_(ds)T_(ds)T_(ds)T_(ks)T_(ks)G_(ks)T_(e) 1341526 1308 1323 2112321138 TAAACCTTCCCTGTGT T_(ks)A_(ks)A_(ks)A_(ds) ^(m)C_(ds)^(m)C_(dS)T_(ds)T_(ds) 23 1745 ^(m)C_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ds)G_(ks)T_(ks)G_(ks)T_(e) 1341527 1175 1190 20990 21005TAAGAGGCATGAAAGG T_(ks)A_(ks)A_(ks)G_(ds)A_(ds)G_(ds)G_(ds)^(m)C_(ds)A_(ds) 36 2751 T_(ds)G_(ds)A_(ds)A_(ks)A_(ks)G_(ks)G_(e)1341530 693 708 12111 12126 ATGAGGTTTTGATACCA_(ks)T_(kS)G_(ks)A_(ds)G_(ds)G_(ds)T_(ds)T_(ds)T_(ds) 20 569T_(ds)G_(ds)A_(ds)T_(ks)A_(ks) ^(m)C_(ks) ^(m)C_(e) 1341531 1336 135121151 21166 ACAGATTGGAATGCTA A_(ks)^(m)C_(ks)A_(ks)G_(ds)A_(ds)T_(dS)T_(ds)G_(ds)G_(ds) 68 1668A_(ds)A_(ds)T_(ds)G_(ks) ^(m)C_(ks)T_(ks)A_(e) 1341557 1347 1362 2116221177 GTGGCATGGCTACAGA G_(ks)T_(ks)G_(ks)G_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds) 38 501 ^(m)C_(ds)T_(ds)A_(ds)^(m)C_(ks)A_(ks)G_(ks)A_(e) 1341561 1346 1361 21161 21176TGGCATGGCTACAGAT T_(ks)G_(ks)G_(ks) ^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)68 423 ^(m)C_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ks)G_(ks)A_(ks)T_(e) 13415731348 1363 21163 21178 TGTGGCATGGCTACAG T_(ks)G_(ks)T_(ks)G_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ds) 25 579 G_(ds) ^(m)C_(ds)T_(ds)A_(ks)^(m)C_(ks)A_(ks)G_(e) 1341576 801 816 15682 15697 GTATTCCATCTATCAGG_(ks)T_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) 51 727 T_(ds)^(m)C_(ds)T_(ds)A_(ds)T_(ks) ^(m)C_(ks)A_(ks)G_(e) 1341608 N/A N/A 1991419929 AGTGCATCTTAAGATA A_(ks)G_(ks)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)^(m)C_(ds) 27 2130 T_(ds)T_(ds)A_(ds)A_(ks)G_(es)A_(ks)T_(es)A_(k)1341610 N/A N/A 19915 19930 GAGTGCATCTTAAGATG_(ks)A_(ks)G_(ds)T_(dS)G_(ds) ^(m)C_(ds)A_(ds)T_(ds) 27 2256^(m)C_(ds)T_(ds)T_(ds)A_(ks)A_(es)G_(ks)A_(es)T_(k) 1341611 N/A N/A18690 18705 CTTTGAGACTCTTGTT^(m)C_(ks)T_(ks)T_(ds)T_(ds)G_(ds)A_(dS)G_(ds)A_(ds) 42 2583^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ks)T_(es)G_(ks)T_(es)T_(k) 1341612 N/A N/A19904 19919 AAGATACCCAGGTTGC A_(ks)A_(ks)G_(ds)A_(ds)T_(ds)A_(ds)^(m)C_(ds) ^(m)C_(ds) 59 2712^(m)C_(ds)A_(ds)G_(ds)G_(ks)T_(es)T_(ks)G_(es) ^(m)C_(k) 1341613 N/A N/A18092 18107 TGATACACCAATGCAG T_(ks)G_(ks)A_(ds)T_(ds)A_(ds)^(m)C_(ds)A_(ds) ^(m)C_(ds) 62 2370 ^(m)C_(ds)A_(ds)A_(ds)T_(ks)G_(es)^(m)C_(ks)A_(es)G_(k) 1341618 N/A N/A 19906 19921 TTAAGATACCCAGGTTT_(ks)T_(ks)A_(ds)A_(ds)G_(ds)A_(ds)Tc_(s)A_(ds) ^(m)C_(ds) 48 163^(m)C_(ds) ^(m)C_(ds)A_(ks)G_(es)G_(ks)T_(es)T_(k) 1341619 N/A N/A 2038820403 CTATAGTAATCACAAG^(m)C_(ks)T_(ks)A_(ds)T_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 36 1644T_(ds) ^(m)C_(ds)A_(ks) ^(m)C_(es)A_(ks)A_(es)G_(k) 1341620 N/A N/A20187 20202 TATTAGAAGTCAGCCCT_(ks)A_(ks)T_(ds)T_(ds)A_(ds)G_(ds)A_(ds)A_(ds)G_(ds) 36 164 T_(ds)^(m)C_(ds)A_(ks)G_(es) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(k) 1341621 N/A N/A20109 20124 AAGACATTCTAGCCTG A_(ks)A_(ks)G_(ds)A_(ds)^(m)C_(ds)A_(dS)T_(dS)T_(ds) 25 2744 ^(m)C_(ds)T_(ds)A_(ds)G_(ks)^(m)C_(es) ^(m)C_(ks)T_(es)G_(k) 1341622 N/A N/A 20197 20212ACATTGCAGTTATTAG A_(ks) ^(m)C_(ks)A_(ds)T_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds) 46 2309 G_(ds)T_(ds)T_(ds)A_(ks)T_(es)T_(ks)A_(es)G_(k)1341623 N/A N/A 20119 20134 TTACAGCATCAAGACA T_(ks)T_(ks)A_(ds)^(m)C_(ds)A_(ds)G_(ds) ^(m)C_(ds)A_(ds) 22 2409 T_(ds)^(m)C_(ds)A_(ds)A_(ks)G_(es)A_(ks) ^(m)C_(es)A_(k) 1341624 N/A N/A 1991619931 GGAGTGCATCTTAAGA G_(ks)G_(ks)A_(ds)G_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ds) 34 2810^(m)C_(ds)T_(ds)T_(ks)A_(es)A_(ks)G_(es)A_(k) 1341625 N/A N/A 200092<X>24 AGAGAGTAATCAGTTTA_(ks)G_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 52 2651 T_(ds)^(m)C_(ds)A_(ks)G_(es)T_(ks)T_(es)T_(k) 1341626 N/A N/A 19905 19920TAAGATACCCAGGTTG T_(ks)A_(ks)A_(ds)G_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds)30 2790 ^(m)C_(ds) ^(m)C_(ds)A_(ds)G_(ks)G_(es)T_(ks)T_(es)G_(k) 1341627N/A N/A 19999 20014 CAGTTTTCCTCATGAT^(m)C_(ks)A_(ks)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) 59 2331^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ks)T_(es)G_(ks)A_(es)T_(k) 1341628 N/A N/A20378 20393 CACAAGTAAGGTAAAG ^(m)C_(ks)A_(ks)^(m)C_(ds)A_(dS)A_(ds)G_(ds)T_(ds)A_(ds) 38 2448A_(ds)G_(ds)G_(ds)T_(ks)A_(es)A_(ks)A_(es)G_(k) 1341629 N/A N/A 1280412819 CTCAGGCTGTAAGAGT ^(m)C_(ks)T_(kS) ^(m)C_(ds)A_(dS)G_(ds)G_(ds)^(m)C_(ds)T_(ds) 10 2240 G_(ds)T_(ds)A_(ds)A_(ks)Gc_(s)A_(ks)G_(es)T_(k)1341630 N/A N/A 14165 14180 GCAAGCCAACAGAGAG G_(ks)^(m)C_(ks)A_(ds)A_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) 12 2556 A_(ds)^(m)C_(ds)A_(ds)G_(ks)A_(es)G_(ks)A_(es)G_(k) 1341631 N/A N/A 1417514190 GCCTTGAATAGCAAGC G_(ks) ^(m)C_(ks)^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds)A_(ds) 16 2063 T_(ds)A_(ds)G_(ds)^(m)C_(ks)A_(es)A_(ks)G_(es) ^(m)C_(k) 1341632 N/A N/A 13959 13974GTCTACCTCTAAGTTA G_(ks)T_(ks) ^(m)C_(ds)T_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ds) 15 2363^(m)C_(ds)T_(ds)A_(ds)A_(ks)G_(es)T_(ks)T_(es)A_(k) 1341633 N/A N/A13949 13964 AAGTTAGCCCCCAGGA A_(ks)A_(ks)G_(ds)T_(ds)T_(ds)A_(ds)G_(ds)^(m)C_(ds) 12 2811 ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)^(m)C_(ks)A_(es)G_(ks)G_(es)A_(k) 1341634 N/A N/A 12496 12511AATTCACCTTGACTAA A_(ks)A_(ks)T_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds) 9 2144 T_(ds)T_(ds)G_(ds)A_(ks) ^(m)C_(es)T_(ks)A_(es)A_(k)1341635 N/A N/A 20479 20494 TAGTGGACTTCATTAGT_(ks)A_(ks)G_(ds)T_(ds)G_(ds)G_(ds)A_(ds) ^(m)C_(dS)T_(ds) 41 2351T_(ds) ^(m)C_(ds)A_(ks)T_(es)T_(ks)A_(es)G_(k) 1341636 N/A N/A 2048920504 CATAACTTCATAGTGG ^(m)C_(ks)A_(ks)T_(ds)A_(ds)A_(ds)^(m)C_(ds)T_(ds)T_(ds) 15 866^(m)C_(ds)A_(ds)T_(ds)A_(ks)G_(es)T_(ks)G_(es)G_(k) 1341637 N/A N/A12794 12809 AAGAGTCAGTATCCTC A_(ks)A_(ks)G_(ds)A_(ds)G_(ds)T_(ds)^(m)C_(ds)A_(ds)G_(ds) 14 2572 T_(ds)A_(ds)T_(ks) ^(m)C_(es)^(m)C_(ks)T_(es) ^(m)C_(k) 1341638 1394 1409 21209 21224CTTGATCTCTTAGCTG ^(m)C_(ks)T_(kS)T_(ks)G_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds) 36 736 ^(m)C_(ds)T_(ds)T_(ds)A_(ds)G_(ks)^(m)C_(ks)T_(ks)G_(e) 1341639 1416 1431 21231 21246 GAGATAAAGCTGCCTGG_(ks)A_(ks)G_(ks)A_(dS)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds) 55 1592^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(ks)G_(e) 1341640 14261441 21241 21256 TGTCCAGGTTGAGATA T_(ks)G_(ks)T_(ks) ^(m)C_(ds)^(m)C_(ds)A_(ds)G_(ds)G_(ds) 45 191T_(ds)T_(ds)G_(ds)A_(ds)G_(ks)A_(ks)T_(ks)A_(e) 1341641 1415 1430 2123021245 AGATAAAGCTGCCTGC A_(ks)G_(ks)A_(ks)T_(ds)A_(ds)A_(ds)A_(ds)G_(ds)^(m)C_(ds) 44 1515 T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks)G_(ks)^(m)C_(e) 1341642 1425 1440 21240 21255 GTCCAGGTTGAGATAA G_(ks)T_(kS)^(m)C_(ks) ^(m)C_(ds)A_(ds)G_(ds)G_(ds)T_(ds) 52 113T_(ds)G_(ds)A_(ds)G_(ds)A_(ks)T_(ks)A_(ks)A_(e) 1341643 791 806 1567215687 TATCAGACTTCTTACG T_(ks)A_(ks)T_(ks) ^(m)C_(ds)A_(ds)G_(ds)A_(ds)^(m)C_(ds) 28 103 T_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ks)A_(ks)^(m)C_(ks)G_(e) 1341644 1398 1413 21213 21228 GAAACTTGATCTCTTAG_(ks)A_(ks)A_(ks)A_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) 79 2717T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ks)T_(ks)T_(ks)A_(e) 1341645 1388 140321203 21218 CTCTTAGCTGTGCACT ^(m)C_(ks)T_(ks)^(m)C_(ks)T_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds) 66 268T_(ds)G_(ds)T_(ds)G_(ds) ^(m)C_(ks)A_(ks) ^(m)C_(ks)T_(e) 1341646 13841399 21199 21214 TAGCTGTGCACTCATT T_(ks)A_(ks)G_(ks)^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 66 1981 ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ks)A_(ks)T_(ks)T_(e) 1341647 N/A N/A 14189 14204TTGAGTTCTCCACTGC T_(ks)T_(ks)G_(ds)A_(ds)G_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ds) 20 2885 ^(m)C_(ds) ^(m)C_(ds)A_(ks)^(m)C_(es)T_(ks)G_(es) ^(m)C_(k) 1341949 N/A N/A 12799 12814GCTGUAAGAGTCAGTA G_(ks)^(m)C_(ks)T_(ks)G_(ds)U_(ys)A_(ds)A_(ds)G_(ds)A_(ds) 28 2886G_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ks)T_(ks)A_(k) 1341950 1088 1103 2090320918 TTGACTGCTGCTAGTG T_(ks)T_(ks)G_(ks)A_(ds)C_(ys)T_(ds)G_(ds)^(m)C_(ds)T_(ds) 40 28 G_(ds) ^(m)C_(ds)T_(ds)A_(dS)G_(ks)T_(ks)G_(k)1341958 N/A N/A 12797 12812 TGTAAGAGTCAGTATCT_(ks)G_(ks)T_(ks)A_(ds)A_(ys)G_(ds)A_(ds)G_(ds)T_(ds) 29 2652^(m)C_(ds)A_(ds)G_(ds)T_(ds)A_(ks)T_(ks) ^(m)C_(k) 1341959 1091 110620906 20921 CGTTUGACTGCTGCTA^(m)C_(ks)G_(ks)T_(ks)T_(ds)U_(ys)G_(ds)A_(ds) ^(m)C_(ds) 54 2887T_(ds)G_(ds) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ks)T_(ks)A_(k) 1341960 N/AN/A 14172 14187 TTGAATAGCAAGCCAAT_(ks)T_(ks)G_(ks)A_(ds)A_(ys)T_(ds)A_(ds)G_(ds) ^(m)C_(ds) 30 1864A_(ds)A_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks)A_(k) 1341961 N/A N/A14175 14190 GCCTUGAATAGCAAGC G_(ks) ^(m)C_(ks)^(m)C_(ks)T_(ds)U_(ys)G_(ds)A_(ds)A_(ds) 12 2888 T_(ds)A_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ks)G_(ks) ^(m)C_(k) 1341962 N/A N/A 13949 13964AAGTUAGCCCCCAGGA A_(ks)A_(ks)G_(ks)T_(ds)U_(yS)A_(dS)G_(ds) ^(m)C_(ds) 02889 ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)G_(ks)G_(ks)A_(k)1341963 N/A N/A 13952 13967 TCTAAGTTAGCCCCCA T_(ks)^(m)C_(ks)T_(ks)A_(ds)A_(ys)G_(ds)T_(d)gT_(ds)A_(ds) 7 928 G_(ds)^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks)A_(k) 1341964 N/AN/A 13956 13971 TACCUCTAAGTTAGCC T_(ks)A_(ks)T_(ks) ^(m)C_(ds)U_(ys)^(m)C_(ds)T_(ds)A_(ds) 13 2890 A_(ds)G_(ds)T_(ds)T_(ds)A_(ds)G_(ks)^(m)C_(ks) ^(m)C_(k) 1341965 N/A N/A 13954 13969 CCTCUAAGTTAGCCCC^(m)C_(ks) ^(m)C_(ks)T_(ks) ^(m)C_(ds)U_(ys)A_(ds)A_(ds)G_(ds) 8 2891T_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(k)1341966 N/A N/A 13959 13974 GTCTACCTCTAAGTTA G_(ks)T_(ks)^(m)C_(ks)T_(ds)A_(ys) ^(m)C_(ds) ^(m)C_(ds)T_(ds) 15 2363^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ks)T_(ks)A_(k) 1341967 N/A N/A12794 12809 AAGAGTCAGTATCCTC A_(ks)A_(ks)G_(ks)A_(ds)Gv_(s)T_(ds)^(m)C_(ds)A_(ds)G_(ds) 55 2572 T_(ds)A_(ds)T_(ds) ^(m)C_(ds)^(m)C_(ks)T_(ks) ^(m)C_(k) 1341968 1202 1217 21017 21032GTATGTTTATGTAAGC G_(kS)T_(ks)A_(ks)T_(ds)G_(ys)T_(dS)T_(ds)T_(ds)A_(ds)66 1511 T_(ds)G_(ds)T_(ds)A_(ds)A_(ks)G_(ks) ^(m)C_(k) 1341969 1200 121521015 21030 ATGTUTATGTAAGCACA_(ks)T_(ks)G_(ks)T_(ds)U_(ys)T_(ds)A_(ds)T_(ds)G_(ds) 45 2892T_(ds)A_(ds)A_(ds)G_(ds) ^(m)C_(ks)A_(ks) ^(m)C_(k) 1341970 N/A N/A14168 14183 ATAGCAAGCCAACAGAA_(ks)T_(ks)A_(ks)G_(ds)C_(ys)A_(ds)A_(ds)G_(ds) ^(m)C_(ds) 1 2633^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ks)G_(ks)A_(k) 1341971 606 621 1049210507 AATAUGGGATGAGGTAA_(ks)A_(ks)T_(ks)A_(ds)U_(ys)G_(ds)G_(ds)G_(ds)A_(ds) 38 2893T_(ds)G_(ds)A_(ds)G_(ds)G_(ks)T_(ks)A_(k) 1341972 1175 1190 20990 21005TAAGAGGCATGAAAGG T_(ks)A_(ks)A_(ks)G_(ds)A_(ys)G_(ds)G_(ds)^(m)C_(ds)A_(ds) 50 2751 T_(ds)G_(ds)A_(ds)A_(ds)A_(ks)G_(ks)G_(k)1341973 1180 1195 20995 21010 GTTTUTAAGAGGCATGG_(ks)T_(kS)T_(ks)T_(ds)U_(ys)T_(ds)A_(ds)A_(ds)G_(ds) 38 2894A_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ks)T_(ks)G_(k) 1341974 N/A N/A 1416514180 GCAAGCCAACAGAGAG G_(ks) ^(m)C_(ks)A_(ks)A_(ds)G_(ys) ^(m)C_(ds)^(m)C_(ds)A_(ds) 26 2556 A_(ds)^(m)C_(ds)A_(ds)G_(ds)A_(ds)G_(ks)A_(ks)G_(k) 1341975 N/A N/A 1417014185 GAATAGCAAGCCAACA G_(ks)A_(ks)A_(ks)T_(ds)A_(ys)G_(ds)^(m)C_(ds)A_(ds)A_(ds) 23 1708 G_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ks)^(m)C_(ks)A_(k) 1341976 N/A N/A 14192 14207 TGATUGAGTTCTCCACT_(ks)G_(ks)A_(ks)T_(ds)U_(ys)G_(ds)A_(ds)G_(ds)T_(ds) 4 2895 T_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(ks) ^(m)C_(k) 1341977 N/A N/A14189 14204 TTGAGTTCTCCACTGC T_(ks)T_(ks)G_(ks)A_(ds)G_(ys)T_(ds)T_(ds)^(m)C_(ds)T_(ds) 18 2885 ^(m)C_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ks)G_(ks) ^(m)C_(k) 1341978 1261 1276 21076 21091AGGTAGCTTTTGTCCA A_(ks)G_(ks)G_(ks)T_(ds)A_(ys)G_(ds)^(m)C_(ds)T_(ds)T_(ds) 59 109 T_(ds)T_(ds)G_(ds)T_(ds) ^(m)C_(ks)^(m)C_(ks)A_(k) 1341979 1259 1274 21074 21089 GTAGCTTTTGTCCACCG_(ks)T_(ks)A_(ks)G_(ds)C_(ys)T_(ds)T_(ds)T_(ds)T_(ds) 64 1978G_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(kS) ^(m)C_(ks) ^(m)C_(k) 13419801258 1273 21073 21088 TAGCUTTTGTCCACCT T_(ks)A_(ks)G_(ks)^(m)C_(ds)U_(ys)T_(ds)T_(ds)T_(ds)G_(ds) 67 2896 T_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k)

Example 4: Design of and Antisense Inhibition by Human HSD17B13 ModifiedOligonucleotides in HepRG Cells

Modified oligonucleotides complementary to an HSD17B13 nucleic acid weresynthesized and tested for their effect on HSD17B13 RNA levels in vitro.specifies the chemistry of each modified oligonucleotide; whereinsubscript ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, subscript‘e’ represents a 2′-MOE sugar moiety, subscript ‘y’ represents a2′-O-methyl sugar moiety, subscript ‘k’ represents a cEt modified sugarmoiety, subscript ‘s’ represents a phosphorothioate internucleosidelinkage, and superscript ‘m’ before the cytosine residue represents a5-methyl cytosine. “Start site” indicates the 5′-most nucleoside of thetarget sequence to which the modified oligonucleotide is complementary.“Stop site” indicates the 3′-most nucleoside of the target sequence towhich the modified oligonucleotide is complementary. As shown in theTables below, the modified oligonucleotide are complementary to eitherthe human HSD17B13 mRNA, designated herein as SEQ ID NO: 1 (GENBANKAccession No. NM_178135.4) or to the human HSD17B13 genomic sequence,designated herein as SEQ ID NO: 2 (the complement of GENBANK AccessionNo. NC_000004.12 truncated from nucleotides 87301001 to 87326000) or toboth. ‘N/A’ indicates that the modified oligonucleotide is notcomplementary to that particular target sequence with 100%complementarity.

The modified oligonucleotides were tested in a series of experimentsusing the same culture conditions. The results for each experiment arepresented in separate tables shown below. Cultured HepaRG cells at adensity of 30,000 cells per well were transfected using electroporationwith 1,000 nM of modified oligonucleotide. After a treatment period ofapproximately 24 hours, RNA was isolated from the cells and HSD17B13 RNAlevels were measured by quantitative real-time RTPCR. Human primer probeset RTS43553 was used to measure RNA levels. HSD17B13 RNA levels wereadjusted according to total RNA content, as measured by RIBOGREEN®.Results are presented as percent inhibition of HSD17B13 relative tountreated control cells. As used herein, a value of ‘0’ indicates thattreatment with the modified oligonucleotide did not inhibit HSD17B13mRNA levels.

TABLE 50 Inhibition of HSD17B13 RNA by modified oligonucleotidestargeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1NO: 2 NO: 2 SEQ Compound Start Stop Start Stop SequenceChemistry Notation % ID Number Site Site Site Site (5′ to 3′) (5′ to 3′)inhibition NO 1245927 N/A N/A 3433 3448 AGTAGATGGTAAGTCAA_(ks)G_(ks)T_(ks)A_(ds)G_(ds)A_(ds)T_(ds) 81 121G_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1246023 N/AN/A 5046 5061 GAGTGAATCATTCAGTG_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds)A_(ds) 83 1526 T_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) A_(ks)G_(ks)T_(k) 1340072 N/AN/A 19913 19928 GTGCATCTTAAGATAC G_(ks)T_(ks)G_(ks)^(m)C_(ds)A_(ds)T_(ds) 47 2806 ^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ks)A_(ks) ^(m)C_(k) 1340095 N/A N/A 19395 19410ATAAGAGATGAGTAGG A_(ks)T_(ks)A_(ks)A_(ds)G_(ds)A_(ds)G_(ds) 56 2897A_(ds)T_(ds)G_(ds)A_(ds)G_(ds)T_(ds)A_(ks) G_(ks)G_(k) 1340097 N/A N/A14604 14619 TGCGAGAAATCTAAGA T_(ks)G_(ks)^(m)C_(ks)G_(ds)A_(ds)G_(ds)A_(ds) 50 2898A_(ds)A_(ds)T_(dsin)C_(ds)T_(ds)A_(ds) A_(ks)G_(ks)A_(k) 1340102 N/A N/A10521 10536 TATAACATGGCTGGCA T_(ks)A_(ks)T_(ks)A_(ds)A_(ds)^(m)C_(ds)A_(ds) 33 2899 T_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ds)G_(ds)G_(ks)^(m)C_(ks)A_(k) 1340109 1432 1447 21247 21262 AAAATATGTCCAGGTTA_(ks)A_(ks)A_(ks)A_(ds)T_(ds)A_(ds)T_(ds) 74 2900 G_(ds)T_(ds)^(m)C_(ds) ^(m)C_(ds)A_(ds)G_(ds) G_(ks)T_(ks)T_(k) 1340134 N/A N/A 99679982 GTAGTGTAAGCTGAGA G_(ks)T_(ks)A_(ks)G_(ds)T_(ds)G_(ds)T_(ds) 81 2901A_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ds)G_(ds) A_(ks)G_(ks)A_(k) 1340137 N/AN/A 18139 18154 ATGTTATCTCAAGTCAA_(ks)T_(ks)G_(ks)T_(ds)T_(ds)A_(ds)T_(ds) 79 2902 ^(m)C_(ds)T_(ds)^(m)C_(ds)A_(ds)A_(ds)G_(ds) T_(ks) ^(m)C_(ks)A_(k) 1340138 1632 164721447 21462 GATTTAAAATAGAGTC G_(ks)A_(ks)T_(ks)T_(ds)T_(ds)A_(ds)A_(ds)46 2903 A_(ds)A_(ds)T_(ds)A_(ds)G_(ds)A_(ds)G_(ks) T_(ks) ^(m)C_(k)1340155 N/A N/A 9442 9457 CTCCCACAAAACTAAC ^(m)C_(ks)T_(ks) ^(m)C_(ks)^(m)C_(ds) ^(m)C_(ds)A_(ds) 13 2904 ^(m)C_(ds)A_(ds)A_(ds)A_(ds)A_(ds)^(m)C_(ds) T_(ds)A_(ks)A_(ks) ^(m)C_(k) 1340172 N/A N/A 11623 11638TTCTGTAGGACTCTGC T_(ks)T_(ks) ^(m)C_(ks)T_(ds)G_(ds)T_(ds)A_(ds) 72 2905G_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) T_(ks)G_(ks) ^(m)C_(k)1340180 N/A N/A 20417 20432 AAAATTATGCCTTGTGA_(ks)A_(ks)A_(ks)A_(ds)T_(ds)T_(ds)A_(ds) 50 2906 T_(ds)G_(ds)^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds) TG_(ks)T_(ks)G_(k) 1340182 N/A N/A14915 14930 TACATTAGCAAGCTAA T_(ks)A_(ks)^(m)C_(ks)A_(ds)T_(ds)T_(ds)A_(ds) 29 2907 G_(ds)^(m)C_(ds)A_(ds)A_(ds)G_(ds) ^(m)C_(ds) T_(ks)A_(ks)A_(k) 1340213 N/AN/A 20593 20608 GCTGAGAGTTATCTGG G_(ks)^(m)C_(ks)T_(ks)G_(ds)A_(ds)G_(ds)A_(ds) 65 2908G_(ds)T_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ks) G_(ks)G_(k) 1340249 N/AN/A 18037 18052 TCATAGTTTATATGGA T_(ks)^(m)C_(ks)A_(ks)T_(ds)A_(ds)G_(ds)T_(ds) 44 2909T_(ds)T_(ds)A_(ds)T_(ds)A_(ds)T_(ds)G_(ks) G_(ks)A_(k) 1340263 N/A N/A13609 13624 TTGAAGACAATACAGG T_(ks)T_(ks)G_(ks)A_(ds)A_(ds)G_(ds)A_(ds)63 2910 ^(m)C_(ds)A_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds) A_(ks)G_(ks)G_(k)1340282 N/A N/A 19535 19550 ATAGGCTAAAATGGTCA_(ks)T_(ks)A_(ks)G_(ds)G_(ds) ^(m)C_(ds)T_(ds) 61 2911A_(ds)A_(ds)A_(ds)A_(ds)T_(ds)G_(ds)G_(ks) T_(ks) ^(m)C_(k) 1340287 N/AN/A 18696 18711 AAAAGACTTTGAGACT A_(ks)A_(ks)A_(ks)A_(ds)G_(ds)A_(ds)^(m)C_(ds) 32 2912 T_(ds)T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)A_(ks)^(m)C_(ks)T_(k) 1340288 N/A N/A 11115 11130 ACAGAGGAGTTTGCAG A_(ks)^(m)C_(ks)A_(ks)G_(ds)A_(ds)G_(ds)G_(ds) 37 2913A_(ds)G_(ds)T_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ks) A_(ks)G_(k) 1340289 13091324 21124 21139 TTAAACCTTCCCTGTG T_(ks)T_(ks)A_(ks)A_(ds)A_(ds)^(m)C_(ds) 22 2807 ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)^(m)C_(ds) T_(ds)G_(ks)T_(ks)G_(k) 1340295 1178 1193 20993 21008TTTTAAGAGGCATGAA T_(ks)T_(ks)T_(ks)T_(ds)A_(ds)A_(ds)G_(ds) 53 2914A_(ds)G_(ds)G_(ds) ^(m)C_(ds)A_(ds)T_(ds)G_(ks) A_(ks)A_(k) 1340301 N/AN/A 20113 20128 CATCAAGACATTCTAG ^(m)C_(ks)A_(ks)T_(ks)^(m)C_(ds)A_(ds)A_(ds) 49 2915 G_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ks)A_(ks)G_(k) 1340306 N/A N/A 19732 19747 AACTGAAGGTCTGAGCA_(ks)A_(ks) ^(m)C_(ks)T_(ds)G_(ds)A_(ds)A_(ds) 55 2916G_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ds)A_(ks) G_(ks) ^(m)C_(k) 1340315N/A N/A 14284 14299 TGAATGTAAAGGCTGGT_(ks)G_(ks)A_(ks)A_(ds)T_(ds)G_(ds)T_(ds) 38 2917A_(ds)A_(ds)A_(ds)G_(ds)G_(ds) ^(m)C_(ds)T_(ks) G_(ks)G_(k) 1340333 17641779 21579 21594 TACAGTTCCTTTTCCT T_(ks)A_(ks)^(m)C_(ks)A_(ds)G_(ds)T_(ds)T_(ds) 68 2918 ^(m)C_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 1340340N/A N/A 6913 6928 TCGGGAAGTTTAGACA T_(ks)^(m)C_(ks)G_(ks)G_(ds)G_(ds)A_(ds)A_(ds) 43 2919G_(ds)T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ks) ^(m)C_(ks)A_(k) 1340341 N/AN/A 6330 6345 GACTTTCATAGGGAGA G_(ks)A_(ks) ^(m)C_(ks)T_(ds)T_(ds)T_(ds)72 2920 ^(m)C_(ds)A_(ds)T_(ds)A_(ds)G_(ds)G_(ds)G_(ds) A_(ks)G_(ks)A_(k)1340346 N/A N/A 11510 11525 ATTATGAGGATCTGGAA_(ks)T_(ksrrks)A_(ds)T_(ds)G_(ds)A_(ds) 49 2921G_(ds)G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds)G_(ks) G_(ks)A_(k) 1340359 N/AN/A 13949 13964 AAGTTAGCCCCCAGGAA_(ks)A_(ks)G_(ks)T_(ds)T_(ds)A_(ds)G_(ds) 36 2811 ^(m)C_(ds) ^(m)C_(ds)^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds) A_(ds)G_(ks)G_(ks)A_(k) 1340362 N/A N/A6734 6749 GATTACCCCTGGCTTT G_(ks)A_(ks)T_(ks)T_(ds)A_(ds) ^(m)C_(ds) 312922 ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ds)G_(ds)G_(ds)^(m)C_(ds)T_(ks)T_(ks)T_(k) 1340391 N/A N/A 12204 12219 TATCATACCACATACCT_(ks)A_(ks)T_(ks) ^(m)C_(ds)A_(ds)T_(ds)A_(ds) 24 2923 ^(m)C_(ds)^(m)C_(ds)A_(ds) ^(m)C_(ds)A_(ds)T_(ds) A_(ks) ^(m)C_(ks) ^(m)C_(k)1340393 N/A N/A 5744 5759 CACTGATTTAGTTGGT ^(m)C_(ks)A_(ks)^(m)C_(ks)T_(ds)G_(ds)A_(ds) 66 2924T_(ds)T_(ds)T_(ds)A_(ds)G_(ds)T_(ds)T_(ds) G_(ks)G_(ks)T_(k) 1340399 N/AN/A 15419 15434 CCAGTAGGTGTGTTTC ^(m)C_(ks) ^(m)_(n)C_(ks)A_(ks)G_(ds)T_(ds)A_(ds) 55 2925G_(ds)G_(ds)T_(ds)G_(ds)T_(ds)G_(ds)T_(ds) T_(ks)T_(ks) ^(m)C_(k)1340403 N/A N/A 5673 5688 GGTCAGTAGAGAGCAT G_(ks)G_(ks)T_(ks)^(m)C_(ds)A_(ds)G_(ds)T_(ds) 79 2926A_(ds)G_(ds)A_(ds)G_(ds)A_(ds)G_(ds) ^(m)C_(ks) A_(ks)T_(k) 1340409  683 698 12101 12116 GATACCAGTTTTTCCC G_(ks)A_(ks)T_(ks)A_(ds) ^(m)C_(ds)^(m)C_(ds) 75 2927 A_(ds)G_(ds)T_(ds)T_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ks)^(m)C_(ks) ^(m)C_(k) 1340411 N/A N/A 9206 9221 AGATGTACACTGACAAA_(ks)G_(ks)A_(ks)T_(ds)G_(ds)T_(ds)A_(ds) 66 2928 ^(m)C_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds)A_(ds) ^(m)C_(ks)A_(ks)A_(k) 1340420 N/A N/A 2019320208 TGCAGTTATTAGAAGT T_(ks)G_(ks) ^(m)C_(ks)A_(ds)G_(ds)T_(ds)T_(ds)46 2929 A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)Ac_(is)A_(ks) G_(ks)T_(k) 1340444N/A N/A 8963 8978 CTCCGTTATAAGTTTC ^(m)C_(ks)T_(ks) ^(m)C_(ks)^(m)C_(ds)G_(ds)T_(ds) 59 2930T_(ds)A_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds) T_(ks)T_(ks) ^(m)C_(k)1340456 N/A N/A 16218 16233 TATAGACTGGGTAGGAT_(ks)A_(ks)T_(ks)A_(ds)G_(ds)A_(ds) ^(m)C_(ds) 61 2808T_(ds)G_(ds)G_(ds)G_(ds)T_(ds)A_(ds)G_(ks) G_(ks)A_(k) 1340460 N/A N/A9775 9790 ACTAGAACTCCCAACC A_(ks)^(m)C_(ks)T_(ks)A_(ds)G_(ds)A_(ds)A_(ds) 20 2931 ^(m)C_(ds)T_(ds)^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) A_(ks) ^(m)C_(ks) ^(m)C_(k)1340467 N/A N/A 8129 8144 TTAGAGTGCTTAGTTCT_(ks)T_(ks)A_(ks)G_(ds)A_(ds)G_(ds)T_(ds) 58 2932 G_(ds)^(m)C_(ds)T_(ds)T_(ds)A_(ds)G_(ds)T_(ks) T_(ks) ^(m)C_(k) 1340473 N/AN/A 3608 3623 TTTAGCAGCTTGGAAG T_(ks)T_(ks)T_(ks)A_(ds)G_(ds)^(m)C_(ds)A_(ds) 43 2933 G_(ds) ^(m)C_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ks)A_(ks)G_(k) 1340474 N/A N/A 16425 16440 TGATATGTCAATACTCT_(ks)G_(ks)A_(ks)T_(ds)A_(ds)T_(ds)G_(ds) 57 2934 T_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ks)T_(ds) ^(m)C_(k) 1340490N/A N/A 10124 10139 GGATATGTCATCTAAAG_(ks)G_(ks)A_(ks)T_(ds)A_(ds)T_(ds)G_(ds) 68 2935 T_(ds)^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) A_(ks)A_(ks)A_(k) 1340494 N/AN/A 5896 5911 GTCCTTTGTATTTCGC G_(ks)T_(ks) ^(m)C_(ks)^(m)C_(ds)T_(ds)T_(ds) 45 2936T_(ds)G_(ds)T_(ds)A_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ks)G_(ks) ^(m)C_(k)1340520 N/A N/A 3701 3716 ATTTTCAGATCCCGTTA_(ks)T_(ks)T_(ks)T_(ds)T_(ds) ^(m)C_(ds)A_(ds) 67 2937G_(ds)A_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds) G_(ks)T_(ks)T_(k)1340530 N/A N/A 3490 3505 TACAGACTAAGGGACC T_(ks)A_(ks)^(m)C_(ks)A_(ds)G_(ds)A_(ds) 68 2938^(m)C_(ds)T_(ds)A_(ds)A_(ds)G_(ds)G_(ds)G_(ds) A_(ks) ^(m)C_(ks)^(m)C_(k) 1340531 N/A N/A 9337 9352 CCTCGATCCTATATAC ^(m)C_(ks)^(m)C_(ks)T_(ks) ^(m)C_(ds)G_(ds)A_(ds) 31 2812 T_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ds)A_(ds)T_(ds) A_(ds)T_(ks)A_(ks) ^(m)C_(k) 1340532 N/AN/A 12801 12816 AGGCTGTAAGAGTCAG A_(ks)G_(ks)G_(ks)^(m)C_(ds)T_(ds)G_(ds)T_(ds) 74 2809A_(ds)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ks) A_(ks)G_(k) 1340565 N/AN/A 5844 5859 CCCCAAACATGGATGT ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ks)^(m)C_(ds)A_(ds)A_(ds) 62 2939 A_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ds)A_(ds) T_(ks)G_(ks)T_(k) 1340586  811 826 15692 15707 TTATTGGTAAGTATTCT_(ks)T_(ks)A_(ks)T_(ds)T_(ds)G_(ds)G_(ds) 17 2940T_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ks) T_(ks) ^(m)C_(k) 1340599 N/AN/A 6599 6614 GGCTACTTTCAAACCT G_(ks)G_(ks) ^(m)C_(ks)T_(ds)A_(ds)^(m)C_(ds) 54 2941 T_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ds)^(m)C_(ks) ^(m)C_(ks)T_(k) 1340600 N/A N/A 8538 8553 GTTTTGCAAGTTTATCG_(ks)T_(ks)T_(ks)T_(ds)T_(ds)G_(ds) ^(m)C_(ds) 73 2942A_(ds)A_(ds)G_(ds)T_(ds)T_(ds)T_(ds)A_(ks) T_(ks) ^(m)C_(k) 1340612 N/AN/A 6450 6465 AGTAGTAATTCTAAACA_(ks)G_(ks)T_(ks)A_(ds)G_(ds)T_(ds)A_(ds) 23 2943 A_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ks) A_(ks) ^(m)C_(k) 1340625 N/A N/A 7527 7542TCCGAAAAAAGTGGAG T_(ks) ^(m)C_(ks) ^(m)C_(ks)G_(ds)A_(ds)A_(ds) 12 2944A_(ds)A_(ds)A_(ds)A_(ds)G_(ds)T_(ds)G_(ds) G_(ks)A_(ks)G_(k) 1340627 N/AN/A 10292 10307 GAGAGAACTTATACAAG_(ks)A_(ks)G_(ks)A_(ds)G_(ds)A_(ds)A_(ds) 37 2945^(m)C_(ds)T_(ds)T_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ks)A_(ks)A_(k) 1340629  77   92 3171 3186 CAGAAGGATTTCTAGG^(m)C_(ks)A_(ks)G_(ks)A_(ds)A_(ds)G_(ds)G_(ds) 43 2946A_(ds)T_(ds)T_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ks) G_(ks)G_(k) 1340633 N/AN/A 4662 4677 CCCGCCCTTAAGTCAT ^(m)C_(ks) ^(m)C_(ks) ^(m)C_(ks)G_(ds)^(m)C_(ds) 45 2947 ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ks)A_(ks)T_(k) 1340643 N/A N/A 5277 5292GCTAGACAATTGCAAA G_(ks) ^(m)C_(ks)T_(ks)A_(ds)G_(ds)A_(ds) 77 2948^(m)C_(ds)A_(ds)A_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ks)A_(ks)A_(k)1340686 N/A N/A 5189 5204 TTCCCAACGCAACAGT T_(ks)T_(ks) ^(m)C_(ks)^(m)C_(ds) ^(m)C_(ds)A_(ds) 60 2949 A_(ds) ^(m)C_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ks)G_(ks)T_(k) 1340694 N/A N/A 56485663 GAGCATTCATCAGATG G_(ks)A_(ks)G_(ks) ^(m)C_(ds)A_(ds)T_(ds)T_(ds) 642950 ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)A_(ds)G_(ds) A_(ks)T_(ks)G_(k)1340698 N/A N/A 6087 6102 AGTTTTCACCTCAGGTA_(ks)G_(ks)T_(ks)T_(ds)T_(ds)T_(ds) ^(m)C_(ds) 82 2951 A_(ds)^(m)C_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)A_(ds) G_(ks)G_(ks)T_(k) 1340709N/A N/A 9116 9131 AGACAGACCAAGTAGC A_(ks)G_(ks)A_(ks)^(m)C_(ds)A_(ds)G_(ds)A_(ds) 21 2952 ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds)G_(ds)T_(ds) A_(ks)G_(ks) ^(m)C_(k) 1340719 N/AN/A 9944 9959 ACCACACTAATGAATC A_(ks) ^(m)C_(ks) ^(m)C_(ks)A_(ds)^(m)C_(ds)A_(ds) 54 2953 ^(m)C_(ds)T_(ds)A_(ds)A_(ds)T_(ds)G_(ds)A_(ds)A_(ks)T_(ks) ^(m)C_(k) 1340726 N/A N/A 6262 6277 TGAGATGGGCAAGGCCT_(ks)G_(ks)A_(ks)G_(ds)A_(ds)T_(ds)G_(ds) 53 2954 G_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds)G_(ds)G_(ks) ^(m)C_(ks) ^(m)C_(k) 1340728 N/A N/A8645 8660 GGCAAGACAGACTGTT G_(ks)G_(ks)^(m)C_(ks)A_(ds)A_(ds)G_(ds)A_(ds) 75 2955 ^(m)C_(ds)A_(ds)G_(ds)A_(ds)^(m)C_(ds)T_(ds) G_(ks)T_(ks)T_(k) 1340729 N/A N/A 14191 14206GATTGAGTTCTCCACT G_(ks)A_(ks)T_(ks)T_(ds)G_(ds)A_(ds)G_(ds) 45 2956T_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) A_(ks)^(m)C_(ks)T_(k) 1340739 N/A N/A 16288 16303 TTAGAATAGTCTTCAGT_(ks)T_(ks)A_(ks)G_(ds)A_(ds)A_(ds)T_(ds) 52 2957 A_(ds)G_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ks)A_(ks)G_(k) 1340752 N/A N/A 9590 9605AGCTGGTAAAGGTAAG A_(ks)G_(ks) ^(m)C_(ks)T_(ds)G_(ds)G_(ds)T_(ds) 55 2958A_(ds)A_(ds)A_(ds)G_(ds)G_(ds)T_(ds)A_(ks) A_(ks)G_(k) 1340755 N/A N/A3995 4010 ATGTAGTGTTTACAAG A_(ks)T_(ks)G_(ks)T_(ds)A_(ds)G_(ds)T_(ds) 582959 G_(ds)T_(ds)T_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ks) A_(ks)G_(k) 1340769N/A N/A 12666 12681 GTTAACCTGCAGCAGA G_(ks)T_(ks)T_(ks)A_(ds)A_(ds)^(m)C_(ds) 51 2960 ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)^(m)C_(ds)A_(ks)G_(ks)A_(k) 1340791 N/A N/A 17953 17968 TAGAAACTGCTCCTCAT_(ks)A_(ks)G_(ks)A_(ds)A_(ds)A_(ds) ^(m)C_(ds) 32 2961 T_(ds)G_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds) T_(ks) ^(m)C_(ks)A_(k) 1340795N/A N/A 7789 7804 GTGACATAACTACTTC G_(ks)T_(ks)G_(ks)A_(ds)^(m)C_(ds)A_(ds)T_(ds) 68 2962 A_(ds)A_(ds) ^(m)C_(ds)T_(ds)A_(ds)^(m)C_(ds) T_(ks)T_(ks) ^(m)C_(k) 1340801 N/A N/A 4246 4261TAAGTGTAAGAGACAT T_(ks)A_(ks)A_(ks)G_(ds)T_(ds)G_(ds)T_(ds) 63 2963A_(ds)A_(ds)G_(ds)A_(ds)G_(ds)A_(ds) ^(m)C_(ks) A_(ks)T_(k) 1340810 N/AN/A 12480 12495 GGAGCTAGATACTCAA G_(ks)G_(ks)A_(ks)G_(ds)^(m)C_(ds)T_(ds)A_(ds) 42 2964 G_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds)T_(ds)^(m)C_(ks)A_(ks)A_(k) 1340819 N/A N/A 18530 18545 TCCTACAGTGCTTAGTT_(ks) ^(m)C_(ks) ^(m)C_(ks)T_(ds)A_(ds) ^(m)C_(ds) 44 2965A_(ds)G_(ds)T_(ds)G_(ds) ^(m)C_(ds)T_(ds)T_(ds) A_(ks)G_(ks)T_(k)1340907 N/A N/A 5121 5136 AAGGAGCCAGTTATGAA_(ks)A_(ks)G_(rks)G_(ds)A_(ds)G_(ds) 57 2966 ^(m)C_(ds)^(m)C_(ds)A_(ds)G_(ds)T_(ds)T_(ds) A_(ds)T_(ks)G_(ks)A_(k) 1340917 N/AN/A 9666 9681 ATGCAGCTATAGGTAG A_(ks)T_(ks)G_(ks) ^(m)C_(ds)A_(ds)G_(ds)41 2967 ^(m)C_(ds)T_(ds)A_(ds)T_(ds)A_(ds)G_(ds)G_(ds) T_(ks)A_(ks)G_(k)

TABLE 51 Inhibition of HSD17B13 RNA by modified oligonucleotidestargeting SEQ ID NO.: 1, and 2 SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1NO: 2 NO: 2 SEQ Compound Start Stop Start Stop SequenceChemistry Notation % ID Number Site Site Site Site (5′ to 3′) (5′ to 3′)inhibition NO 1245927 N/A N/A 3433 3448 AGTAGATGGTAAGTCAA_(ks)G_(ks)T_(ks)A_(ds)G_(ds)A_(ds)T_(ds) 77 121G_(ds)G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1246023 N/AN/A 5046 5061 GAGTGAATCATTCAGTG_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds)A_(ds) 81 1526 T_(ds)^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) A_(ks)G_(ks)T_(k) 1341164 610625 N/A N/A GAACAATATGGGATGA G_(ks)A_(ks)A_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds) 49 1735A_(ds)T_(ds)G_(ds)G_(ds)G_(ks)A_(es)T_(ks) G_(es)A_(k) 1341172 812 82715693 15708 CTTATTGGTAAGTATT^(m)C_(ks)T_(ks)T_(ds)A_(ds)T_(ds)T_(ds)G_(ds) 9 1350G_(ds)T_(ds)A_(ds)A_(ds)G_(ks)T_(es)A_(ks) T_(es)T_(k) 1341178 698 71312116 12131 GAGACATGAGGTTTTG G_(ks)A_(ks)G_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ds) 49 725 G_(ds)A_(ds)G_(ds)G_(ds)T_(ks)T_(es)T_(ks)T_(es)G_(k) 1341186 1079 1094 20894 20909 GCTAGTGCCAAACCAA G_(ks)^(m)C_(ks)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds) 62 1354 ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)A_(k) 13411881017 1032 20832 20847 CAGCATTGATTCGAAA ^(m)C_(ks)A_(ks)G_(ds)^(m)C_(ds)A_(ds)T_(ds) 58 263 T_(ds)G_(ds)A_(ds)T_(ds)T_(ds)^(m)C_(ks)G_(es) A_(ks)A_(es)A_(k) 1341192 1200 1215 21015 21030ATGTTTATGTAAGCAC A_(ks)T_(ks)G_(ds)T_(ds)T_(ds)T_(ds)A_(ds) 61 2622T_(ds)G_(ds)T_(ds)A_(ds)A_(ks)G_(es) ^(m)C_(ks) A_(es) ^(m)C_(k) 13411961088 1103 20903 20918 TTGACTGCTGCTAGTG T_(ks)T_(ks)G_(ds)A_(ds)^(m)C_(ds)T_(ds)G_(ds) 29 28 ^(m)C_(ds)T_(ds)G_(ds)^(m)C_(ds)T_(ks)A_(es) G_(ks)T_(es)G_(k) 1341199 1083 1098 20898 20913TGCTGCTAGTGCCAAA T_(ks)G_(ks) ^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds) 40 1665T_(ds)A_(ds)G_(ds)T_(ds)G_(ds) ^(m)C_(ks) ^(m)C_(es)A_(ks)A_(es)A_(k)1341203 1311 1326 21126 21141 TCTTAAACCTTCCCTG T_(ks)^(m)C_(ks)T_(ds)T_(ds)A_(ds)A_(ds)A_(ds) 24 2160 ^(m)C_(ds)^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ks) ^(m)C_(es) ^(m)C_(ks)T_(es)G_(k)1341208 1315 1330 21130 21145 ACAGTCTTAAACCTTC A_(ks)^(m)C_(ks)A_(ds)G_(ds)T_(ds) ^(m)C_(ds) 46 110T_(ds)T_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es)T_(ks)T_(es)^(m)C_(k) 1341209 1257 1272 21072 21087 AGCTTTTGTCCACCTT A_(ks)G_(ks)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ds) 62 1822 G_(ds)T_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ks) ^(m)C_(es) ^(m)C_(ks)T_(es)T_(k) 1341215 1323 133821138 21153 CTACTTGAACAGTCTT ^(m)C_(ks)T_(ks)A_(ds)^(m)C_(ds)T_(ds)T_(ds) 47 734 G_(ds)A_(ds)A_(ds)^(m)C_(ds)A_(ds)G_(ks)T_(es) ^(m)C_(ks)T_(es)T_(k) 1341221 1327 134221142 21157 AATGCTACTTGAACAG A_(ks)A_(ks)T_(ds)G_(ds)^(m)C_(ds)T_(ds)A_(ds) 39 1045 ^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ks)A_(es)^(m)C_(ks)A_(es)G_(k) 1341224 1337 1352 21152 21167 TACAGATTGGAATGCTT_(ks)A_(ks) ^(m)C_(ds)A_(ds)G_(ds)A_(ds)T_(ds) 35 1746T_(ds)G_(ds)G_(ds)A_(ds)A_(ks)T_(es)G_(ks) ^(m)C_(es)T_(k) 1341229 13311346 21146 21161 TTGGAATGCTACTTGAT_(ks)T_(ks)G_(ds)G_(ds)A_(ds)A_(ds)T_(ds) 54 1279 G_(ds)^(m)C_(ds)T_(ds)A_(ds) ^(m)C_(ks)T_(es) T_(ks)G_(es)A_(k) 1341230 13511366 21166 21181 TTCTGTGGCATGGCTA T_(ks)T_(ks)^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds) 50 812 G_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ks)G_(es) ^(m)C_(ks)T_(es)A_(k) 1341235 13551370 21170 21185 GATATTCTGTGGCATG G_(ks)A_(ks)T_(ds)A_(ds)T_(ds)T_(ds)^(m)C_(ds) 52 1046 T_(ds)G_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(es)A_(ks)T_(es)G_(k) 1341245 1391 1406 21206 21221 GATCTCTTAGCTGTGCG_(ks)A_(ks)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds) 45 502T_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks)G_(es) T_(ks)G_(es) ^(m)C_(k)1341249 1359 1374 21174 21189 TGTTGATATTCTGTGGT_(ks)G_(ks)T_(ds)T_(ds)G_(ds)A_(ds)T_(ds) 54 1358 A_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ks)G_(es)T_(ks) G_(es)G_(k) 1341252 1431 1446 21246 21261AAATATGTCCAGGTTG A_(ks)A_(ks)A_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 61 581T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)G_(ks)G_(es) T_(ks)T_(es)G_(k) 13412531419 1434 21234 21249 GTTGAGATAAAGCTGCG_(ks)T_(ks)T_(ds)G_(ds)A_(ds)G_(ds)A_(ds) 40 1748T_(ds)A_(ds)A_(ds)A_(ds)G_(ks) ^(m)C_(es)T_(ks) G_(es) ^(m)C_(k) 13412561423 1438 21238 21253 CCAGGTTGAGATAAAG ^(m)C_(ks)^(m)C_(ks)A_(ds)G_(ds)G_(ds)T_(ds) 55 33T_(ds)G_(ds)A_(ds)G_(ds)A_(ds)T_(ks)A_(es) A_(ks)A_(es)G_(k) 13412641492 1507 21307 21322 CACCGTTTTGGGCTAA ^(m)C_(ks)A_(ks) ^(m)C_(ds)^(m)C_(ds)G_(ds)T_(ds) 42 1516 T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)G_(ks)^(m)C_(es) T_(ks)A_(es)A_(k) 1341270 1602 1617 21417 21432ATGTATCTTATAAGAC A_(ks)T_(ks)G_(ds)T_(ds)A_(ds)T_(ds) ^(m)C_(ds) 18 1751T_(ds)T_(ds)A_(ds)T_(ds)A_(ks)A_(es)G_(ks) A_(es) ^(m)C_(k) 1341272 15011516 21316 21331 ATAGAGTTGCACCGTTA_(ks)T_(ks)A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) 45 192 T_(ds)G_(ds)^(m)C_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es) G_(ks)T_(es)T_(k) 1341276 16171632 21432 21447 CGGTCACCTTTCATAA ^(m)C_(ks)G_(ks)G_(ds)T_(ds)^(m)C_(ds)A_(ds) 70 36 ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ks) A_(es)T_(ks)A_(es)A_(k) 1341278 1621 1636 21436 21451GAGTCGGTCACCTTTC G_(ks)A_(ks)G_(ds)T_(ds) ^(m)C_(ds)G_(ds)G_(ds) 62 350T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es) T_(ks)T_(es)^(m)C_(k) 1341282 1625 1640 21440 21455 AATAGAGTCGGTCACCA_(ks)A_(ks)T_(ds)A_(ds)G_(ds)A_(ds)G_(ds) 13 662 T_(ds)^(m)C_(ds)G_(ds)G_(ds)T_(ks) ^(m)C_(es) A_(ks) ^(m)C_(es) ^(m)C_(k)1341289 1629 1644 21444 21459 TTAAAATAGAGTCGGTT_(ks)T_(ks)A_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 51 973A_(ds)G_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(es)G_(ks) G_(es)T_(k) 1341293 17131728 21528 21543 AACATCTCTGGGACCA A_(ks)A_(ks) ^(m)C_(ds)A_(ds)T_(ds)^(m)C_(ds) 36 273 T_(ds) ^(m)C_(ds)T_(ds)G_(ds)G_(ds)G_(ks)A_(es)^(m)C_(ks) ^(m)C_(es)A_(k) 1341294 1708 1723 21523 21538CTCTGGGACCAAGGAT ^(m)C_(ks)T_(ks) ^(m)C_(ds)T_(ds)G_(ds)G_(ds) 39 1908G_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ks) G_(es)G_(ks)A_(es)T_(k)1341301 1777 1792 21592 21607 ATGTAATAGCCAGTACA_(ks)T_(ks)G_(ds)T_(ds)A_(ds)A_(ds)T_(ds) 47 430 A_(ds)G_(ds)^(m)C_(ds) ^(m)C_(ds)A_(ks)G_(es) T_(ks)A_(es) ^(m)C_(k) 1341304 17661781 21581 21596 AGTACAGTTCCTTTTC A_(ks)G_(ks)T_(ds)A_(ds)^(m)C_(ds)A_(ds)G_(ds) 40 1597 T_(ds)T_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ks)T_(es) T_(ks)T_(es) ^(m)C_(k) 1341311 1773 1788 2158821603 AATAGCCAGTACAGTT A_(ks)A_(ks)T_(ds)A_(ds)G_(ds) ^(m)C_(ds) 36 118^(m)C_(ds)A_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ks) A_(es)G_(ks)T_(es)T_(k)1341319 1781 1796 21596 21611 TCTTATGTAATAGCCA T_(ks)^(m)C_(ks)T_(ds)T_(ds)A_(ds)T_(ds)G_(ds) 65 742T_(ds)A_(ds)A_(ds)T_(ds)A_(ks)G_(es) ^(m)C_(ks) ^(m)C_(es)A_(k) 13413222254 2269 22069 22084 CAAGAGGATAGTCCAT^(m)C_(ks)A_(ks)A_(ds)G_(ds)A_(ds)G_(ds)G_(ds) 22 510A_(ds)T_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(es) ^(m)C_(ks)A_(es)T_(k) 13413262245 2260 22060 22075 AGTCCATGCAAAAGCA A_(ks)G_(ks)T_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds) 52 120 T_(ds)G_(ds) ^(m)C_(ds)A_(ds)A_(ds)A_(ks)A_(es)G_(ks) ^(m)C_(es)A_(sk) 1341327 2191 2206 22006 22021 GTCTTGATGTAGTGGGG_(ks)T_(ks) ^(M)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds) 18 1132T_(ds)G_(ds)T_(ds)A_(ds)G_(ks)T_(es)G_(ks) G_(es)G_(k) 1341333 N/A N/A9518 9533 CTACACTAATATTGAG ^(m)C_(ks)T_(ks)A_(ds) ^(m)C_(ds)A_(ds)^(m)C_(ds) 5 59 T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)T_(ks)T_(es)G_(ks)A_(es)G_(k) 1341338 2355 2370 22170 22185 TTATAACTACAAGAGGT_(ks)T_(ks)A_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) 55 1289 T_(ds)A_(ds)^(m)C_(ds)A_(ds)A_(ks)G_(es)A_(ks) G_(es)G_(k) 1341345 N/A N/A 1185311868 AGCAGAATTGTGAACG A_(ks)G_(ks) ^(m)C_(ds)A_(ds)G_(ds)A_(ds)A_(ds)31 844 T_(ds)T_(ds)G_(ds)T_(ds)G_(ks)A_(es)A_(ks) ^(m)C_(es)G_(k)1341357 N/A N/A 12421 12436 TGGTAACGGTGATCAAT_(ks)G_(ks)G_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds) 26 67G_(ds)G_(ds)T_(ds)G_(ds)A_(ks)T_(es) ^(m)C_(ks) A_(es)A_(k) 1341368 N/AN/A 16131 16146 GCTCCATAATAATAGC G_(ks) ^(m)C_(ks)T_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds) 15 2665 T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)A_(ks)T_(es)A_(ks)G_(es) ^(m)C_(k) 1341374 N/A N/A 18099 18114 CTGAAATTGATACACC^(m)C_(ks)T_(ks)G_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 45 393T_(ds)G_(ds)A_(ds)T_(ds)A_(ks) ^(m)C_(es)A_(ks) ^(m)C_(es) ^(m)C_(k)1341378 N/A N/A 17991 18006 GTTAGTATAGTTATCTG_(ks)T_(ks)T_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 51 1171T_(ds)A_(ds)G_(ds)T_(ds)T_(ks)A_(es)T_(ks) ^(m)C_(es)T_(k) 1341381 N/AN/A 19911 19926 GCATCTTAAGATACCC G_(ks) ^(m)C_(ks)A_(ds)T_(ds)^(m)C_(ds)T_(ds) 41 553 T_(ds)A_(ds)A_(ds)G_(ds)A_(ds)T_(ks)A_(es)^(m)C_(k) ^(m)C_(es) ^(m)C_(sk) 1341385 N/A N/A 19907 19922CTTAAGATACCCAGGT ^(m)C_(ks)T_(ks)T_(ds)A_(ds)A_(ds)G_(ds)A_(ds) 34 241T_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks)A_(es) G_(ks)G_(es)T_(k)1341390 N/A N/A 20114 20129 GCATCAAGACATTCTA G_(ks)^(m)C_(ks)A_(ds)T_(ds) ^(m)C_(ds)A_(ds) 43 1565 A_(ds)G_(ds)A_(ds)^(m)C_(ds)A_(ds)T_(ks)T_(es) ^(m)C_(ks)T_(es)A_(k) 1341398 N/A N/A 2019420209 TTGCAGTTATTAGAAG T_(ks)T_(ks)G_(ds) ^(m)C_(ds)A_(ds)G_(ds)T_(ds)27 2123 T_(ds)A_(ds)T_(ds)T_(ds)A_(ks)G_(es)A_(ks) A_(es)G_(k) 1341403N/A N/A 12801 12816 AGGCTGTAAGAGTCAG A_(ks)G_(ks)G_(ds)^(m)C_(ds)T_(ds)G_(ds)T_(ds) 38 2809A_(ds)A_(ds)G_(ds)A_(ds)G_(ks)T_(es) ^(m)C_(ks) A_(es)G_(k) 1341405 N/AN/A 12501 12516 GCAGAAATTCACCTTG G_(ks)^(m)C_(ks)A_(ds)G_(ds)A_(ds)A_(ds)A_(ds) 53 1002 T_(ds)T_(ds)^(m)C_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(es) T_(ks)T_(es)G_(k) 1341409 N/A N/A20422 20437 ACAGTAAAATTATGCC A_(ks)^(m)C_(ks)A_(ds)G_(ds)T_(ds)A_(ds)A_(ds) 28 477A_(ds)A_(ds)T_(ds)T_(ds)A_(ks)T_(es)G_(ks) ^(m)C_(es) ^(m)C_(k) 1341411N/A N/A 14194 14209 TGTGATTGAGTTCTCCT_(ks)G_(ks)T_(ds)G_(ds)A_(ds)T_(ds)T_(ds) 11 2020G_(ds)A_(ds)G_(ds)T_(ds)T_(ks) ^(m)C_(es)T_(ks) ^(m)C_(es) ^(m)C_(k)1341414 N/A N/A 14168 14183 ATAGCAAGCCAACAGA A_(ks)T_(ks)A_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds) 23 2633 G_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ks)^(m)C_(es) A_(ks)G_(es)A_(k) 1341528 1075 1090 20890 20905GTGCCAAACCAATGTT G_(ks)T_(ks)G_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) 38 1042A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ks) T_(es)G_(ks)T_(es)T_(k)1341536 801 816 15682 15697 GTATTCCATCTATCAGG_(ks)T_(ks)A_(ds)T_(ds)T_(ds) ^(m)C_(ds) 48 727 ^(m)C_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds)A_(ks) T_(es) ^(m)C_(ks)A_(es)G_(k) 1341537 791 80615672 15687 TATCAGACTTCTTACG T_(ks)A_(ks)T_(ds)^(m)C_(ds)A_(ds)G_(ds)A_(ds) 32 103 ^(m)C_(ds)T_(ds)T_(ds)^(m)C_(ds)T_(ks)T_(es) A_(ks) ^(m)C_(es)G_(k) 1341542 1319 1334 2113421149 TTGAACAGTCTTAAAC T_(ks)T_(ks)G_(ds)A_(ds)A_(ds) ^(M)C_(ds)A_(ds)37 422 G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ks)A_(es)A_(ks) A_(es) ^(m)C_(k)1341544 1264 1279 21079 21094 GGGAGGTAGCTTTTGTG_(i)c_(s)G_(i)c_(s)G_(ds)A_(ds)G_(ds)G_(ds) 66 343 T_(ds)A_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ks)T_(es) T_(ks)G_(es)T_(k) 1341548 1384 1399 2119921214 TAGCTGTGCACTCATT T_(ks)A_(ks)G_(ds) ^(m)C_(ds)T_(ds)G_(ds)T_(ds)53 1981 G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es)A_(ks)T_(es)T_(k) 1341550 1398 1413 21213 21228 GAAACTTGATCTCTTAG_(ks)A_(ks)A_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ds) 54 2717G_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ks) ^(m)C_(es) T_(ks)T_(es)A_(k) 13415531346 1361 21161 21176 TGGCATGGCTACAGAT T_(ks)G_(ks)G_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ds) 58 423 G_(ds) ^(m)C_(ds)T_(ds)A_(ds)^(m)C_(ks)A_(es) G_(ks)A_(es)T_(k) 1341559 1488 1503 21303 21318GTTTTGGGCTAATGAA G_(ks)T_(ks)T_(ds)T_(ds)T_(ds)G_(ds)G_(ds) 42 1204G_(ds) ^(m)C_(ds)T_(ds)A_(ds)A_(ks)T_(es)G_(ks) A_(es)A_(k) 1341562 14961511 21311 21326 GTTGCACCGTTTTGGG G_(ks)T_(ks)T_(ds)G_(ds)^(m)C_(ds)A_(ds) 35 1827 ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds)T_(ds)T_(ks)T_(es)G_(ks)G_(es)G_(k) 1341571 1717 1732 21532 21547 TCTAAACATCTCTGGGT_(ks) ^(m)C_(ks)T_(ds)A_(ds)A_(ds)A_(ds) 21 2287 ^(m)C_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds) ^(m)C_(ks) T_(es)G_(ks)G_(es)G_(k) 1341586 2184 219921999 22014 TGTAGTGGGAGTCGGA T_(ks)G_(ks)T_(ds)A_(ds)G_(ds)T_(ds)G_(ds)27 587 G_(ds)G_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(es)G_(ks) G_(es)A_(k)1341587 1726 1741 21541 21556 CTAAAATTGTCTAAAC^(m)C_(ks)T_(ks)A_(ds)A_(ds)A_(ds)A_(ds)T_(ds) 19 2590T_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ks)A_(es)A_(ks) A_(es) ^(m)C_(k) 1341590N/A N/A 9337 9352 CCTCGATCCTATATAC ^(m)C_(ks) ^(m)C_(ks)T_(ds)^(m)C_(ds)G_(ds)A_(ds) 3 2812 T_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ds)A_(ds)T_(ks) A_(es)T_(ks)A_(es) ^(m)C_(k) 1341593 N/AN/A 9961 9976 TAAGCTGAGAGTTCTA T_(ks)A_(ks)A_(ds)G_(ds)^(m)C_(ds)T_(ds)G_(ds) 29 2499 A_(ds)G_(ds)A_(ds)G_(ds)T_(ks)T_(es)^(m)C_(ks) T_(es)A_(k) 1341594 N/A N/A 11568 11583 TGACAATGGTTGATAGT_(ks)G_(ks)A_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds) 37 1700G_(ds)G_(ds)T_(ds)T_(ds)G_(ks)A_(es)T_(ks) A_(es)G_(k) 1341597 N/A N/A9971 9986 TTGAGTAGTGTAAGCT T_(ks)T_(ks)G_(ds)A_(ds)G_(ds)T_(ds)A_(ds) 292346 G_(ds)T_(ds)G_(ds)T_(ds)A_(ks)A_(es)G_(ks) ^(m)C_(es)T_(k) 1341598N/A N/A 16282 16297 TAGTCTTCAGCAAAGT T_(ks)A_(ks)G_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds) 35 2632 ^(m)C_(ds)A_(ds)G_(ds)^(m)C_(ds)A_(ks)A_(es) A_(ks)G_(es)T_(k) 1341599 N/A N/A 16377 16392ACCAAACTTCCAGCAG A_(ks) ^(m)C_(ks) ^(m)C_(ds)A_(ds)A_(ds)A_(ds) 32 1948^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks) G_(es)^(m)C_(ks)A_(es)G_(k) 1341605 N/A N/A 15491 15506 TTAATGCCACCCTACCT_(ks)T_(ks)A_(ds)A_(ds)T_(ds)G_(ds) ^(m)C_(ds) 11 2304 ^(m)C_(ds)A_(ds)^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(es) A_(ks) ^(m)C_(es) ^(m)C_(k)1341606 N/A N/A 14204 14219 CAGATTATTATGTGAT^(m)C_(ks)A_(ks)G_(ds)A_(ds)T_(ds)T_(ds)A_(ds) 31 2723T_(ds)T_(ds)A_(ds)T_(ds)G_(ks)T_(es)G_(ks) A_(es)T_(k) 1341609 N/A N/A17986 18001 TATAGTTATCTTCTCA T_(ks)A_(ks)T_(ds)A_(ds)G_(ds)T_(ds)T_(ds)45 2295 A_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ks) ^(m)C_(es) ^(m)T_(ks)C_(es)A_(k) 1341616 N/A N/A 17996 18011 ATGAAGTTAGTATAGTA_(ks)T_(ks)G_(ds)A_(ds)A_(ds)G_(ds)T_(ds) 34 1483T_(ds)A_(ds)G_(ds)T_(ds)A_(ks)T_(es)A_(ks) G_(es)T_(k)

TABLE 52Inhibition of HSD17B13 RNA by modified oligonucleotides targeting SEQ ID NO.: 1, and 2SEQ ID SEQ ID SEQ ID SEQ ID SEQ Compound NO: 1 NO: 1 NO: 2 NO: 2Sequence Chemistry Notation % ID Number Start Site Stop Site Start SiteStop Site (5′ to 3′) (5′ to 3′) inhibition NO 1245927 N/A N/A 3433 3448AGTAGATGGTAAGTCA A_(ks)G_(ks)T_(ks)A_(ds)G_(ds)A_(ds)T_(ds)G_(ds) 79 121G_(ds)T_(ds)A_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)A_(k) 1246023 N/A N/A5046 5061 GAGTGAATCATTCAGTG_(ks)A_(ks)G_(ks)T_(ds)G_(ds)A_(ds)A_(ds)T_(ds) 89 1526^(m)C_(ds)A_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks) T_(k) 1341650 12641279 21079 21094 GGGAGGTAGCTTTTGTG_(ks)G_(ks)G_(ks)A_(ds)G_(ys)G_(ds)T_(ds)A_(ds) 17 343 G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)T_(ks)G_(ks)T_(k) 1341653 1316 1331 2113121146 AACAGTCTTAAACCTT A_(ks)A_(ks) ^(m)C_(ks)A_(ds)G_(ys)T_(ds)^(m)C_(ds) 75 188 T_(ds)T_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks)T_(k) 1341660 1328 1343 21143 21158 GAATGCTACTTGAACAG_(ks)A_(ks)A_(ks)T_(ds)G_(ys) ^(m)C_(ds)T_(ds) 48 1123 A_(ds)^(m)C_(ds)T_(ds)T_(ds)G_(ds)A_(ds)A_(ks) ^(m)C_(ks)A_(k) 1341664 13201335 21135 21150 CTTGAACAGTCTTAAA^(m)C_(ks)T_(ks)T_(ks)G_(ds)A_(ys)A_(ds) ^(m)C_(ds) 49 500A_(ds)G_(ds)T_(ds) ^(m)C_(ds)T_(ds)T_(ds)A_(ks) A_(ks)A_(k) 1341667 13121327 21127 21142 GTCTUAAACCTTCCCT G_(ks)T_(ks)^(m)C_(ks)T_(ds)U_(ys)A_(ds)A_(ds) 35 2968 A_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 13416701333 1348 21148 21163 GATTGGAATGCTACTTG_(ks)A_(ks)T_(ks)T_(ds)G_(ys)G_(ds)A_(ds)A_(ds) 48 1435 T_(ds)G_(ds)^(m)C_(ds)T_(ds)A_(ds) ^(m)C_(ks)T_(ks) T_(k) 1341676 1324 1339 2113921154 GCTACTTGAACAGTCT G_(ks) ^(m)C_(ks)T_(ks)A_(ds)C_(ys)T_(ds)T_(ds)82 811 G_(ds)A_(ds)A_(ds) ^(m)C_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)T_(k)1341678 1356 1371 21171 21186 TGATATTCTGTGGCATT_(ks)G_(ks)A_(ks)T_(ds)A_(ys)T_(ds)T_(ds) 61 1124^(m)C_(ds)T_(ds)G_(ds)T_(ds)G_(ds)G_(ds) ^(m)C_(ks) A_(ks)T_(k) 13416801347 1362 21162 21177 GTGGCATGGCTACAGAG_(iss)T_(ks)G_(iss)G_(ds)C_(ys)A_(ds)T_(ds) 49 501 G_(ds)G_(ds)^(m)C_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ks) G_(ks)A_(k) 1341683 1340 135521155 21170 GGCTACAGATTGGAAT G_(ks)G_(ks) ^(m)C_(ks)T_(ds)A_(ys)^(m)C_(ds)A_(ds) 40 1980G_(ds)A_(ds)T_(ds)T_(ds)G_(ds)G_(ds)A_(ks)A_(ks) T_(k) 1341690 1364 137921179 21194 GTTCUTGTTGATATTC G_(ks)T_(ks)T_(ks)^(m)C_(ds)U_(ys)T_(ds)G_(ds) 70 2969T_(ds)T_(ds)G_(ds)A_(ds)T_(ds)A_(ds)T_(ks)T_(ks) ^(m)C_(k) 1341696 13521367 21167 21182 ATTCUGTGGCATGGCT A_(ks)T_(ks)T_(ks)^(m)C_(ds)U_(ys)G_(ds)T_(ds) 59 2970 G_(ds)G_(ds)^(m)C_(ds)A_(ds)T_(ds)G_(ds)G_(ks) ^(m)C_(ks)T_(k) 1341699 1387 140221202 21217 TCTTAGCTGTGCACTC T_(ks) ^(m)C_(ks)T_(ks)T_(ds)A_(ys)G_(ds)^(m)C_(ds) 71 190 T_(ds)G_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k) 1341705 1393 1408 21208 21223 TTGAUCTCTTAGCTGTT_(ks)T_(ks)G_(ks)A_(ds)U_(ys) ^(m)C_(ds)T_(ds) 50 2971^(m)C_(ds)T_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ks) G_(ks)T_(k) 13417111420 1435 21235 21250 GGTTGAGATAAAGCTGG_(ks)G_(ks)T_(ks)T_(ds)G_(ys)A_(ds)G_(ds)A_(ds) 57 1826T_(ds)A_(ds)A_(ds)A_(ds)G_(ds) ^(m)C_(ks)T_(ks)G_(k) 1341714 1425 144021240 21255 GTCCAGGTTGAGATAA G_(ks)T_(ks) ^(m)C_(ks)^(m)C_(ds)A_(ys)G_(ds)G_(ds) 68 113T_(ds)T_(ds)G_(ds)A_(ds)G_(ds)A_(ds)T_(ks)A_(ks) A_(k) 1341718 1461 147621276 21291 CTAGGGAAATCTTTCA^(m)C_(ks)T_(ks)A_(ks)G_(ds)G_(ys)G_(ds)A_(ds) 19 659 A_(ds)A_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ks) ^(m)C_(ks)A_(k) 1341721 693 708 12111 12126ATGAGGTTTTGATACC A_(ks)T_(ks)G_(ks)A_(ds)G_(ys)G_(ds)T_(ds)T_(ds) 49 569T_(ds)T_(ds)G_(ds)A_(ds)T_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(k) 1341725 14151430 21230 21245 AGATAAAGCTGCCTGCA_(ks)G_(ks)A_(ks)T_(ds)A_(ys)A_(ds)A_(ds)G_(ds) 35 1515^(m)C_(ds)T_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks)G_(ks) ^(m)C_(k)1341728 1489 1504 21304 21319 CGTTUTGGGCTAATGA^(m)c_(ks)G_(ks)T_(ks)T_(ds)U_(ys)T_(ds)G_(ds) 34 2972 G_(ds)G_(ds)^(m)C_(ds)T_(ds)A_(ds)A_(ds)T_(ks) G_(ks)A_(k) 1341731 1497 1512 2131221327 AGTTGCACCGTTTTGG A_(ks)G_(ks)T_(ks)T_(ds)G_(ys) ^(m)C_(ds)A_(ds)38 1905 ^(m)C_(ds) ^(m)C_(ds)G_(ds)T_(ds)T_(ds)T_(ds)T_(ks) G_(ks)G_(k)1341736 1493 1508 21308 21323 GCACCGTTTTGGGCTA G_(ks) ^(m)C_(ks)A_(ks)^(m)C_(ds)C_(ys)G_(ds)T_(ds) 67 1593T_(ds)T_(ds)T_(ds)G_(ds)G_(ds)G_(ds) ^(m)C_(ks) T_(ks)A_(k) 1341738 16221637 21437 21452 AGAGUCGGTCACCTTT A_(ks)G_(ks)A_(ks)G_(ds)U_(ys)^(m)C_(ds)G_(ds) 55 2973 G_(ds)T_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds)T_(ks) T_(ks)T_(k) 1341744 1504 1519 21319 21334AGAAUAGAGTTGCACC A_(ks)G_(ks)A_(ks)A_(ds)U_(ys)A_(ds)G_(ds)A_(d) 49 2974_(s)G_(ds)T_(ds)T_(ds)G_(ds) ^(m)C_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(k)1341748 1614 1629 21429 21444 TCACCTTTCATAATGT T_(ks) ^(m)C_(ks)A_(ks)^(m)C_(ds)C_(ys)T_(ds)T_(ds)T 47 2109 _(ds)^(m)C_(ds)A_(ds)T_(ds)A_(ds)A_(ds)T_(ks)G_(ks) T_(k) 1341754 1618 163321433 21448 TCGGUCACCTTTCATA T_(ks) ^(m)C_(ks)G_(ks)G_(ds)U_(ys)^(m)C_(ds)A_(ds) 21 2975 ^(m)C_(ds) ^(m)C_(ds)T_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ks) T_(ks)A_(k) 1341761 1630 1645 21445 21460TTTAAAATAGAGTCGG T_(ks)T_(ks)T_(ks)A_(ds)A_(ys)A_(ds)A_(ds)T_(ds) 771051 A_(ds)G_(ds)A_(ds)G_(ds)T_(ds) ^(m)C_(ks)G_(ks)G_(k) 1341764 16261641 21441 21456 AAATAGAGTCGGTCACA_(ks)A_(ks)A_(ks)T_(ds)A_(ys)G_(ds)A_(ds)G_(ds) 63 740 T_(ds)^(m)C_(ds)G_(ds)G_(ds)T_(ds) ^(m)C_(ks)A_(ks) ^(m)C_(k) 1341767 17141729 21529 21544 AAACATCTCTGGGACC A_(ks)A_(ks)A_(ks)^(m)C_(ds)A_(ys)T_(ds) ^(m)C_(ds) 66 2129 T_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ds)G_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(k) 13417681710 1725 21525 21540 ATCTCTGGGACCAAGG A_(ks)T_(ks)^(m)C_(ks)T_(ds)C_(ys)T_(ds)G_(ds) 52 37 G_(ds)G_(ds)A_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ks) G_(ks)G_(k) 1341773 1718 1733 21533 21548GTCTAAACATCTCTGG G_(ks)T_(ks) ^(m)C_(ks)T_(ds)A_(ys)A_(ds)A_(ds) 47 429^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ks) G_(ks)G_(k)1341781 1768 1783 21583 21598 CCAGUACAGTTCCTTT ^(m)C_(ks)^(m)C_(ks)A_(ks)G_(ds)U_(ys)A_(ds) ^(m)C_(ds) 51 2976A_(ds)G_(ds)T_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)T_(ks) T_(ks)T_(k) 13417831750 1765 21565 21580 CTGTGTTAGCTTTAAT^(m)C_(ks)T_(ks)G_(ks)T_(ds)G_(ys)T_(ds)T_(ds) 41 1286 A_(ds)G_(ds)^(m)C_(ds)T_(ds)T_(ds)T_(ds)A_(ks) A_(ks)T_(k) 1341787 794 809 1567515690 ATCTATCAGACTTCTT A_(ks)T_(ks) ^(m)C_(ks)T_(ds)A_(ys)T_(ds)^(m)C_(ds) 34 2728 A_(ds)G_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ks)T_(ks)T_(k) 1341789 1778 1793 21593 21608 TATGUAATAGCCAGTAT_(ks)A_(ks)T_(ks)G_(ds)U_(ys)A_(ds)A_(ds)T_(ds) 43 2977 A_(ds)G_(ds)^(m)C_(ds) ^(m)C_(ds)A_(ds)G_(ks)T_(ks) A_(k) 1341792 1774 1789 2158921604 TAATAGCCAGTACAGT T_(ks)A_(ks)A_(ks)T_(ds)A_(ys)G_(ds) ^(m)C_(ds)51 196 ^(m)C_(ds)A_(ds)G_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ks) G_(ks)T_(k)1341801 2186 2201 22001 22016 GATGUAGTGGGAGTCGG_(ks)A_(ks)T_(ks)G_(ds)U_(ys)A_(ds)G_(ds)T_(ds) 35 2978G_(ds)G_(ds)G_(ds)A_(ds)G_(ds)T_(ks) ^(m)C_(ks)G_(k) 1341806 2193 220822008 22023 TAGTCTTGATGTAGTGT_(ks)A_(ks)G_(ks)T_(ds)C_(ys)T_(ds)T_(ds)G_(ds) 56 1288A_(ds)T_(ds)G_(ds)T_(ds)A_(ds)G_(ks)T_(ks)G_(k) 1341807 1782 1797 2159721612 TTCTUATGTAATAGCC T_(ks)T_(ks) ^(m)C_(ks)T_(ds)U_(ys)A_(ds)T_(ds)66 2979 G_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ds)G_(ks) ^(m)C_(ks) ^(m)C_(k)1341816 2257 2272 22072 22087 AAACAAGAGGATAGTC A_(ks)A_(ks)A_(ks)^(m)C_(ds)A_(ys)A_(ds)G_(ds) 53 744A_(ds)G_(ds)G_(ds)A_(ds)T_(ds)A_(ds)G_(ks)T_(ks) ^(m)C_(k) 1341817 22472262 22062 22077 ATAGUCCATGCAAAAG A_(ks)T_(ks)A_(ks)G_(ds)U_(ys)^(m)C_(ds) ^(m)C_(ds) 57 2980 A_(ds)T_(ds)G_(ds)^(m)C_(ds)A_(ds)A_(ds)A_(ks) A_(ks)G_(k) 1341820 N/A N/A 9511 9526AATAUTGAGGCACTGG A_(ks)A_(ks)T_(ks)A_(ds)U_(ys)T_(ds)G_(ds)A_(ds) 482981 G_(ds)G_(ds) ^(m)C_(ds)A_(ds) ^(m)C_(ds)T_(ks)G_(ks) G_(k) 1341827N/A N/A 9330 9345 CCTAUATACATCCAAG ^(m)C_(ks)^(m)C_(ks)T_(ks)A_(ds)U_(ys)A_(ds)T_(ds) 39 2982 A_(ds)^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks) A_(ks)G_(k) 1341830N/A N/A 9598 9613 ATGTGAAGAGCTGGTAA_(ks)T_(ks)G_(ks)T_(ds)G_(ys)A_(ds)A_(ds)G_(ds) 26 527 A_(ds)G_(ds)^(m)C_(ds)T_(ds)G_(ds)G_(ks)T_(ks)A_(k) 1341832 N/A N/A 9964 9979GTGTAAGCTGAGAGTT G_(ks)T_(ks)G_(ks)T_(ds)A_(ys)A_(ds)G_(ds) 55 2760^(m)C_(ds)T_(ds)G_(ds)A_(ds)G_(ds)A_(ds)G_(ks) T_(ks)T_(k) 1341840 N/AN/A 11543 11558 TGACAATGGTTGCCAC T_(ks)G_(ks)A_(ks)^(m)C_(ds)A_(ys)A_(ds)T_(ds) 55 1233 G_(ds)G_(ds)T_(ds)T_(ds)G_(ds)^(m)C_(ds) ^(m)C_(ks) A_(ks) ^(m)C_(k) 1341842 N/A N/A 11548 11563TCTCUTGACAATGGTT T_(ks) ^(m)C_(ks)T_(ks) ^(m)C_(ds)U_(ys)T_(ds)G_(ds) 622983 11573 11588 A_(ds) ^(m)C_(ds)A_(ds)A_(ds)T_(ds)G_(ds)G_(ks)T_(ks)T_(k) 1341845 N/A N/A 11858 11873 GATTAAGCAGAATTGTG_(ks)A_(ks)T_(ks)T_(ds)A_(ys)A_(ds)G_(ds) 28 1156^(m)C_(ds)A_(ds)G_(ds)A_(ds)A_(ds)T_(ds)T_(ks) G_(ks)T_(k) 1341847 805820 15686 15701 GTAAGTATTCCATCTAG_(ks)T_(ks)A_(ks)A_(ds)G_(ys)T_(ds)A_(ds)T_(ds) 43 1038 T_(ds)^(m)C_(ds) ^(m)C_(ds)A_(ds)T_(ds) ^(m)C_(ks)T_(ks) A_(k) 1341851 N/A N/A14196 14211 TATGUGATTGAGTTCTT_(ks)A_(ks)T_(ks)G_(ds)U_(ys)G_(ds)A_(ds)T_(ds) 21 2984T_(ds)G_(ds)A_(ds)G_(ds)T_(ds)T_(ks) ^(m)C_(ks)T_(k) 1341853 N/A N/A12416 12431 ACGGUGATCAAATGTA A_(ks)^(m)C_(ks)G_(ks)G_(ds)U_(ys)G_(ds)A_(ds)T 18 2985 _(ds)^(m)C_(ds)A_(ds)A_(ds)A_(ds)T_(ds)G_(ks)T_(ks) A_(k) 1341855 N/A N/A12426 12441 CAGGGTGGTAACGGTG^(m)C_(ks)A_(ks)G_(ks)G_(ds)G_(ys)T_(ds)G_(ds) 29 2729G_(ds)T_(ds)A_(ds)A_(ds) ^(m)C_(ds)G_(ds)G_(ks) T_(ks)G_(k) 1341860 N/AN/A 16134 16149 GATGCTCCATAATAAT G_(ks)A_(ks)T_(ks)G_(ds)C_(ys)T_(ds)^(m)C_(ds) 24 2049 ^(m)C_(ds)A_(ds)T_(ds)A_(ds)A_(ds)T_(ds)A_(ks)A_(ks)T_(k) 1341861 N/A N/A 14914 14929 ACATUAGCAAGCTAAG A_(ks)^(m)C_(ks)A_(ks)T_(ds)U_(ys)A_(ds)G_(ds) 23 2986^(m)C_(ds)A_(ds)A_(ds)G_(ds) ^(m)C_(ds)T_(ds)A_(ks) A_(ks)G_(k) 1341862N/A N/A 15494 15509 GCATUAATGCCACCCT G_(ks)^(m)C_(ks)A_(ks)T_(ds)U_(ys)A_(ds)A_(ds) 32 2987 T_(ds)G_(ds) ^(m)C_(ds)^(m)C_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 1341870 N/A N/A16287 16302 TAGAATAGTCTTCAGCT_(ks)A_(ks)G_(ks)A_(ds)A_(ys)T_(ds)A_(ds)G_(ds) 30 1403 T_(ds)^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ks)G_(ks) ^(m)C_(k) 1341877 N/A N/A16124 16139 AATAATAGCTCTATTGA_(ks)A_(ks)T_(ks)A_(ds)A_(ys)T_(ds)A_(ds)G_(ds) 16 2410^(m)C_(ds)T_(ds) ^(m)C_(ds)T_(ds)A_(ds)T_(ks)T_(ks) G_(k) 1341882 N/AN/A 17992 18007 AGTTAGTATAGTTATCAG_(ks)T_(ks)T_(ds)A_(ys)G_(ds)T_(ds)A_(ds) 42 1249T_(ds)A_(dS)G_(ds)T_(ds)T_(ds)A_(ks)T_(ks) ^(m)C_(k) 1341887 N/A N/A16380 16395 CCAACCAAACTTCCAG ^(m)C_(ks) ^(m)C_(ks)A_(ks)A_(ds)C_(ys)^(m)C_(ds)A_(ds) 30 2539 A_(ds)A_(ds) ^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)^(m)C_(ks) A_(ks)G_(k) 1341889 N/A N/A 17987 18002 GTATAGTTATCTTCTCG_(ks)T_(ks)A_(ks)T_(ds)A_(ys)G_(ds)T_(ds)T_(ds) 54 937 A_(ds)T_(ds)^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ks)T_(ks) ^(m)C_(k) 1341890 1082 109720897 20912 GCTGCTAGTGCCAAAC G_(ks)^(m)C_(ks)T_(ks)G_(ds)C_(ys)T_(ds)A_(ds) 39 1587 G_(ds)T_(ds)G_(ds)^(m)C_(ds) ^(m)C_(ds)A_(ds)A_(ks) A_(ks) ^(m)C_(k) 1341895 N/A N/A 1809918114 CTGAAATTGATACACC ^(m)C_(ks)T_(ks)G_(ks)A_(ds)A_(ys)A_(ds)T_(ds) 71393 T_(ds)G_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ds)A_(ks) ^(m)C_(ks) ^(m)C_(k)1341896 N/A N/A 17997 18012 TATGAAGTTAGTATAGT_(ks)A_(ks)T_(ks)G_(ds)A_(ys)A_(ds)G_(ds)T_(ds) 27 1560T_(ds)A_(ds)G_(ds)T_(ds)A_(ds)T_(ks)A_(ks)G_(k) 1341900 N/A N/A 1991119926 GCATCTTAAGATACCC G_(ks) ^(m)C_(ks)A_(ks)T_(ds)C_(ys)T_(ds)T_(ds)65 553 A_(ds)A_(ds)G_(ds)A_(ds)T_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks)^(m)C_(k) 1341907 N/A N/A 18697 18712 CAAAAGACTTTGAGAC^(m)C_(ks)A_(ks)A_(ks)A_(ds)A_(ys)G_(ds)A_(ds) 25 2186^(m)C_(ds)T_(ds)T_(ds)T_(ds)G_(ds)A_(ds)G_(ks) A_(ks) ^(m)C_(k) 1341908N/A N/A 19915 19930 GAGTGCATCTTAAGAT G_(ks)A_(ks)G_(ks)T_(ds)G_(ys)^(m)C_(ds)A_(ds) 7 2256 T_(ds) ^(m)C_(ds)T_(ds)T_(ds)A_(ds)A_(ds)G_(ks)A_(ks)T_(k) 1341914 N/A N/A 19907 19922 CTTAAGATACCCAGGT^(m)C_(ks)T_(ks)T_(ks)A_(ds)A_(ys)G_(ds)A_(ds) 50 241 T_(ds)A_(ds)^(m)C_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ds) G_(ks)G_(ks)T_(k) 1341919 N/A N/A20109 20124 AAGACATTCTAGCCTGA_(ks)A_(ks)G_(ks)A_(ds)C_(ys)A_(ds)T_(ds)T_(ds) 54 2744^(m)C_(ds)T_(ds)A_(ds)G_(ds) ^(m)C_(ds) ^(m)C_(ks)T_(ks) G_(k) 1341923N/A N/A 20119 20134 TTACAGCATCAAGACA T_(ks)T_(ks)A_(ks)^(m)C_(ds)A_(ys)G_(ds) ^(m)C_(ds) 46 2409 A_(ds)T_(ds)^(m)C_(ds)A_(ds)A_(ds)G_(ds)A_(ks) ^(m)C_(ks)A_(k) 1341924 1078 109320893 20908 CTAGUGCCAAACCAAT ^(m)C_(ks)T_(ks)A_(ks)G_(ds)U_(ys)G_(ds)^(m)C_(ds) 45 2988 ^(m)C_(ds)A_(ds)A_(ds)A_(ds) ^(m)C_(ds) ^(m)C_(ds)A_(ks)A_(ks)T_(k) 1341928 N/A N/A 20194 20209 TTGCAGTTATTAGAAGT_(ks)T_(ks)G_(ks) ^(m)C_(ds)A_(ys)G_(ds)T_(ds) 17 2123T_(ds)A_(ds)T_(ds)T_(ds)A_(ds)G_(ds)A_(ks) A_(ks)G_(k) 1341930 N/A N/A20383 20398 GTAAUCACAAGTAAGG G_(ks)T_(ks)A_(ks)A_(ds)U_(ys)^(m)C_(ds)A_(ds) 20 2989 ^(m)C_(ds)A_(ds)A_(ds)G_(ds)T_(ds)A_(ds)A_(ks)G_(ks)G_(k) 1341941 N/A N/A 20489 20504 CATAACTTCATAGTGG^(m)C_(ks)A_(ks)T_(ks)A_(ds)A_(ys) ^(m)C_(ds)T_(ds) 38 866 T_(ds)^(m)C_(ds)A_(ds)T_(ds)A_(ds)G_(ds)T_(ks) G_(ks)G_(k) 1341942 1074 108920889 20904 TGCCAAACCAATGTTT T_(ks)G_(ks) ^(m)C_(ks)^(m)C_(ds)A_(ys)A_(ds)A_(ds) 35 2673 ^(m)C_(ds)^(m)C_(ds)A_(ds)A_(ds)T_(ds)G_(ds)T_(ks) T_(ks)T_(k) 1341948 N/A N/A12503 12518 TTGCAGAAATTCACCT T_(ks)T_(ks)G_(ks)^(m)C_(ds)A_(ys)G_(ds)A_(ds) 29 2528 A_(ds)A_(ds)T_(ds)T_(ds)^(m)C_(ds)A_(ds) ^(m)C_(ks) ^(m)C_(ks)T_(k) 1341953 1086 1101 2090120916 GACTGCTGCTAGTGCC G_(ks)A_(ks) ^(m)C_(ks)T_(ds)G_(ys)^(m)C_(ds)T_(ds) 60 1899 G_(ds) ^(m)C_(ds)T_(ds)A_(ds)G_(ds)T_(ds)G_(ks)^(m) C_(ks) ^(m)C_(k) 1341957 N/A N/A 20479 20494 TAGTGGACTTCATTAGT_(ks)A_(ks)G_(ks)T_(ds)G_(ys)G_(ds)A_(ds) 34 2351^(m)C_(ds)T_(ds)T_(ds) ^(m)C_(ds)A_(ds)T_(ds)T_(ks) A_(ks)G_(k)

Example 5: Dose-Dependent Inhibition of Human HSD17B13 in HepaRG Cellsby Modified Oligonucleotides

Certain modified oligonucleotides described in the studies aboveexhibiting significant in vitro inhibition of HSD17B13 RNA were selectedand tested at various doses in HepaRG cells.

The modified oligonucleotides were tested in a series of experimentsusing the same culture conditions. The results for each experiment arepresented in separate tables shown below. Cultured HepaRG cells at adensity of 30,000-35,000 cells per well were transfected usingelectroporation with modified oligonucleotides diluted to differentconcentrations as specified in the tables below. After a treatmentperiod of approximately 24 hours, HSD17B13 RNA levels were measured aspreviously described using the Human HSD17B13 primer-probe set RTS43553.HSD17B13 RNA levels were normalized to total RNA content, as measured byhuman GAPDH. Results are presented in the tables below as percentinhibition of HSD17B13, relative to untreated control cells. Dataindicated as “N.D.” (no data) means that no data is available for thattreatment with that compound.

The half maximal inhibitory concentration (IC₅₀) of each modifiedoligonucleotide was calculated using a linear regression on a log/linearplot of the data in excel and is also presented in the Tables below.

TABLE 53 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1245094 0 5 75 68 N.D. 0.3 1245641 5 16 52 75 80 0.4 1245744 5 11 40 8187 0.4 1245822 0 0 57 78 93 0.1 1245901 1 14 38 55 78 0.8 1245927 8 4276 83 92 0.2 1245952 25 34 51 70 86 0.2 1245979 4 0 38 64 75 0.8 12460051 14 60 64 78 0.5 1246134 0 50 75 79 N.D. 0.2 1246135 10 10 42 68 88 0.51246161 18 20 63 75 86 0.3 1246550 14 28 58 76 88 0.3 1246706 60 69 6876 N.D. 0.02

TABLE 54 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1245096 3 17 70 85 N.D. 0.2 1245097 4 40 75 80 76 0.2 1245565 2 0 26 5665 1.5 1245798 16 37 57 82 90 0.2 1245825 0 11 44 64 81 0.6 1245851 0 945 69 84 0.6 1245927 0 25 56 79 82 0.4 1245928 7 42 67 89 95 0.2 124598012 43 94 84 N.D. 0.1 1246059 1 15 44 68 81 0.5 1246084 4 18 69 89 93 0.21246110 10 41 71 90 N.D. 0.1 1246111 0 22 44 79 83 0.4 1246162 33 31 7188 94 0.1 1246163 1 17 42 73 92 0.4

TABLE 55 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 19 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1245098 25 27 71 80 71 0.2 1245463 0 0 20 63 78 0.9 1245696 15 30 52 7489 0.3 1245800 0 30 55 82 82 0.3 1245904 12 19 51 73 97 0.3 1245927 3 1148 68 76 0.6 1245930 7 26 58 77 89 0.3 1245957 0 0 54 75 86 0.5 12459827 25 45 78 92 0.3 1245983 0 18 42 67 90 0.5 1246035 0 2 51 73 75 0.61246113 12 0 47 75 84 0.6 1247023 0 23 46 75 90 0.4 1247048 9 22 41 7484 0.4 1247075 0 0 4 50 68 2.0

TABLE 56 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1245075 20 50 62 75 86 0.1 1245829 18 33 58 83 94 0.2 1245855 16 21 5978 89 0.3 1245927 0 21 54 69 76 0.5 1245932 22 24 56 90 94 0.2 124593323 24 63 76 89 0.2 1245958 12 31 43 87 84 0.3 1245959 1 10 46 65 90 0.51245984 9 37 62 76 93 0.2 1246036 15 33 65 80 95 0.2 1246063 16 29 53 8485 0.2 1246115 0 38 66 88 92 0.2 1246140 20 2 54 75 86 0.5 1246192 0 1752 72 89 0.5 1247024 16 45 82 89 97 0.1

TABLE 57 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1245076 0 0 32 66 83 0.6 1245415 0 0 22 65 88 0.9 1245649 8 23 49 79 970.3 1245857 0 2 35 74 91 0.6 1245927 4 25 57 82 86 0.3 1245960 14 34 5478 88 0.2 1245986 2 2 30 78 95 0.4 1245987 26 32 58 82 91 0.2 1246013 00 27 68 83 0.8 1246064 19 36 63 74 92 0.2 1246116 17 41 75 92 95 0.11246169 0 0 30 55 86 1.0 1246195 0 0 26 63 82 0.9 1246610 5 0 2 57 821.3 1247078 3 4 28 66 93 0.6

TABLE 58 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1245105 0 0 24 61 88 0.8 1245651 3 22 49 78 89 0.3 1245676 0 0 34 67 910.7 1245806 28 27 51 69 91 0.2 1245807 1 9 47 80 90 0.4 1245858 16 39 6686 96 0.2 1245927 0 22 46 79 89 0.4 1245988 8 26 40 65 85 0.5 1246066 2641 63 86 94 0.1 1246067 0 0 40 51 85 0.9 1246093 0 0 24 64 86 0.71246144 5 30 43 78 86 0.3 1246145 0 3 40 72 85 0.6 1246248 28 32 62 8692 0.1 1247029 0 0 11 36 73 1.9

TABLE 59 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1245080 7 13 39 70 87 0.5 1245081 4 28 44 72 85 0.4 1245106 0 28 46 8081 0.4 1245809 0 0 1 48 77 1.6 1245886 0 4 21 62 80 0.9 1245927 16 29 6484 90 0.2 1245964 16 22 48 72 95 0.3 1245990 15 4 29 61 86 0.7 1245991 09 26 63 83 0.8 1246068 14 31 49 73 92 0.3 1246095 10 16 46 69 88 0.41246121 0 18 37 76 86 0.5 1246173 3 26 58 83 89 0.3 1246562 5 19 26 7088 0.5

TABLE 60 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1245212 3 1 43 63 88 0.6 1245680 0 0 22 64 82 0.9 1245681 0 17 58 80 940.3 1245888 17 22 41 72 87 0.4 1245927 0 16 52 78 93 0.4 1245967 0 9 4162 89 0.6 1246019 17 26 62 92 91 0.2 1246070 7 31 46 74 94 0.3 1246123 016 37 58 83 0.7 1246226 12 30 56 86 89 0.2 1246227 0 6 0 55 78 1.41246824 0 0 17 40 81 1.5 1246902 0 17 40 74 86 0.5 1246903 35 35 60 6884 0.2 1246929 0 18 40 65 87 0.6

TABLE 61 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1245085 18 21 49 79 95 0.3 1245162 19 5 41 78 97 0.4 1245579 0 8 39 6587 0.6 1245656 20 33 47 80 83 0.3 1245682 23 42 53 87 93 0.2 1245838 9 028 77 92 0.5 1245916 1 25 26 60 82 0.7 1245927 14 36 76 77 86 0.21245968 24 43 69 88 88 0.1 1245969 0 9 32 67 74 0.9 1246124 7 12 31 7690 0.5 1246203 0 0 21 58 87 1.0 1246489 2 14 44 86 86 0.4 1246853 0 0 1652 77 1.3 1247061 0 12 32 70 93 0.5

TABLE 62 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1245580 3 9 49 58 89 0.5 1245607 0 16 33 77 87 0.5 1245684 35 51 77 9296 0.1 1245685 13 25 59 80 93 0.2 1245736 0 0 45 81 95 0.6 1245737 13 2353 83 94 0.3 1245919 0 0 0 72 90 1.0 1245927 0 9 37 84 77 0.4 1245996 2953 74 91 97 0.1 1245997 16 31 54 79 90 0.2 1246022 49 54 80 93 94 0.01246023 0 40 89 86 95 0.2 1246048 12 0 73 73 97 0.3 1246074 7 43 73 8494 0.2 1246075 0 0 41 70 88 0.7

TABLE 63 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1245141 12 30 57 84 90 0.2 1245374 29 7 43 65 85 0.4 1245660 7 12 36 7394 0.4 1245738 36 38 61 80 88 0.1 1245790 50 61 68 87 95 <0.2 1245927 023 58 85 90 0.3 1245972 24 39 58 79 90 0.2 1245973 0 26 41 66 75 0.51245998 12 10 43 78 89 0.4 1245999 0 19 60 87 88 0.3 1246025 35 54 84 9489 0.0 1246051 4 26 54 78 92 0.3 1246128 37 38 58 84 92 0.1 1246701 0 412 20 40 5.0 1246909 0 17 27 66 86 0.7

TABLE 64 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1245142 0 9 40 64 78 0.8 1245246 15 32 33 74 91 0.3 1245610 28 44 61 8297 0.1 1245715 0 0 37 65 86 0.9 1245844 38 37 53 75 89 0.1 1245927 11 2764 75 81 0.3 1245975 0 11 48 71 82 0.5 1246027 0 2 15 71 85 0.8 124605236 41 57 79 85 0.1 1246053 0 0 9 56 74 1.5 1246104 21 40 64 77 91 0.21246105 0 0 3 47 73 1.8 1246130 35 13 54 78 91 0.2 1246157 44 37 62 7891 0.1 1246391 0 0 2 48 83 1.5

TABLE 65 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1245092 9 20 39 68 89 0.4 1245639 0 0 21 65 85 0.8 1245716 20 27 40 6986 0.4 1245927 0 0 25 74 64 1.2 1245976 9 29 57 77 86 0.3 1245977 0 2144 76 94 0.4 1246002 38 51 64 79 91 0.1 1246028 0 0 19 56 80 1.2 12460290 18 50 73 86 0.4 1246081 5 19 48 75 88 0.4 1246185 13 15 43 62 79 0.61246314 3 8 36 72 92 0.5 1246340 28 32 37 58 85 0.4 1246705 1 14 20 4270 1.8 1246861 0 0 7 25 63 5.0

TABLE 66 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1246023 9 21 57 83 87 0.3 1340071 0 0 0 56 88 1.3 1340085 0 0 27 68 910.8 1340154 0 20 48 80 90 0.4 1340360 0 0 0 51 42 3.8 1340385 4 35 69 8272 0.3 1340448 0 0 27 78 74 0.9 1340543 5 15 62 78 86 0.3 1340546 0 1240 65 56 1.2 1340549 0 4 50 78 92 0.4 1340601 0 0 31 54 81 1.1 1340684 00 31 58 84 0.9 1340704 0 8 25 69 83 0.8 1340762 0 13 41 71 79 0.71340878 1 1 30 79 85 0.6

TABLE 67 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1246023 0 20 55 82 88 0.4 1340206 0 22 55 71 90 0.4 1340208 12 12 51 6992 0.4 1340226 0 0 43 73 96 0.6 1340260 0 0 33 56 78 1.0 1340268 0 0 3555 90 0.9 1340334 0 5 30 67 86 0.8 1340397 0 0 49 73 88 0.7 1340555 1 1341 63 76 0.7 1340585 0 13 47 77 74 0.6 1340603 18 16 47 69 85 0.41340647 14 35 76 83 94 0.2 1340789 10 14 32 73 83 0.5 1340834 14 18 4874 79 0.4 1340895 0 19 32 65 87 0.6

TABLE 68 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1246023 0 25 47 76 85 0.4 1340168 6 0 32 80 90 0.6 1340401 4 11 50 78 790.4 1340449 26 8 59 81 93 0.3 1340548 0 17 51 78 92 0.4 1340626 0 5 4580 90 0.5 1340646 6 31 57 67 58 0.6 1340653 2 0 38 69 77 0.8 1340780 623 36 73 83 0.5 1340820 20 35 55 84 88 0.2 1340821 0 0 21 40 60 2.71340847 9 20 45 60 88 0.5 1340857 0 0 11 46 66 2.3 1340859 14 32 47 7184 0.3 1340908 16 33 60 84 92 0.2

TABLE 69 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1246023 0 16 42 80 87 0.5 1340153 0 18 38 75 82 0.5 1340227 0 21 57 7090 0.4 1340435 14 27 57 78 90 0.3 1340441 6 14 32 70 74 0.7 1340493 1323 54 70 88 0.3 1340510 11 13 27 66 87 0.6 1340511 0 0 7 52 74 1.61340572 19 23 53 75 89 0.3 1340630 20 25 42 75 87 0.3 1340670 16 24 5174 93 0.3 1340782 0 26 54 77 92 0.3 1340840 0 3 23 43 67 1.9 1340848 0 030 71 91 0.7 1340861 22 34 47 74 90 0.2

TABLE 70 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1246023 3 22 55 79 84 0.3 1340159 10 13 49 83 80 0.4 1340481 0 0 34 6482 0.8 1340502 0 4 37 71 87 0.6 1340564 5 10 34 72 85 0.5 1340635 7 2140 79 82 0.4 1340649 0 0 42 69 89 0.6 1340672 0 20 47 72 76 0.6 134074312 18 46 80 90 0.3 1340779 5 7 39 68 40 0.6 1340793 3 24 66 86 91 0.21340796 0 19 61 88 84 0.3 1340799 16 34 72 86 89 0.2 1340827 16 31 48 7281 0.3 1340881 10 28 52 59 79 0.4

TABLE 71 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1246023 0 20 42 58 79 0.7 1341183 11 18 27 53 57 2.0 1341190 0 3 29 5348 2.4 1341193 11 27 53 63 68 0.5 1341195 15 13 12 61 71 1.2 1341239 160 27 62 83 0.7 1341262 0 4 36 52 78 0.9 1341273 6 18 38 63 81 0.61341303 29 21 44 61 90 0.3 1341313 9 33 58 67 85 0.3 1341315 8 28 52 7982 0.3 1341342 24 25 37 51 81 0.6 1341348 15 25 43 71 70 0.5 1341391 0 235 49 70 1.3 1341547 13 2 40 61 83 0.6

TABLE 72 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1246023 19 1 38 77 89 0.4 1341026 10 20 43 73 83 0.4 1341032 0 13 14 7492 0.6 1341035 5 0 36 62 74 1.0 1341036 23 28 53 78 93 0.2 1341038 17 2557 76 85 0.3 1341052 6 13 52 69 79 0.5 1341062 0 23 47 66 79 0.5 13410950 17 51 61 81 0.6 1341108 28 34 58 81 83 0.2 1341146 6 0 39 66 70 0.91341206 28 25 45 81 87 0.2 1341260 23 24 37 66 78 0.5 1341283 8 23 40 6790 0.4 1341308 18 29 54 71 86 0.3

TABLE 73 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1246023 0 0 47 66 89 0.6 1340983 0 0 26 55 45 3.1 1340995 1 17 37 66 620.9 1341011 0 0 34 50 81 1.0 1341043 0 3 40 50 44 2.2 1341050 0 7 39 5576 0.9 1341057 6 9 39 57 78 0.8 1341068 0 0 11 46 79 1.5 1341075 0 0 039 55 3.1 1341118 0 8 13 31 74 2.2 1341145 0 17 37 69 83 0.6 1341154 0 047 43 79 1.0 1341244 10 0 21 55 68 1.5 1341335 0 0 25 51 55 2.4 13415104 17 34 57 66 1.0

TABLE 74 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1246023 1 20 59 67 88 0.4 1340992 0 0 0 51 76 1.8 1341004 0 12 31 55 770.9 1341022 15 18 25 65 84 0.6 1341048 1 15 43 74 85 0.5 1341077 8 16 3854 71 0.9 1341104 0 23 38 64 79 0.6 1341140 12 17 41 64 82 0.5 134115113 31 52 71 80 0.3 1341271 8 0 43 65 80 0.7 1341318 23 17 49 61 55 1.01341436 0 23 46 64 77 0.6 1341437 3 0 16 60 88 0.9 1341654 0 24 53 66 690.6 1341668 7 25 42 56 82 0.6

TABLE 75 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1246023 2 24 40 70 92 0.4 1341651 19 35 41 67 85 0.3 1341655 0 0 13 7089 0.9 1341671 13 27 35 66 91 0.4 1341675 9 22 46 77 76 0.4 1341686 2 231 61 78 0.9 1341703 16 14 33 52 58 1.8 1341735 12 32 54 71 84 0.31341742 13 26 39 66 84 0.4 1341797 0 0 34 65 91 0.6 1341815 0 21 20 6575 0.9 1341839 25 16 39 60 87 0.5 1341899 14 28 42 66 77 0.5 1341911 729 46 67 90 0.4 1341913 0 2 0 48 59 3.2

TABLE 76 Multi-dose assay of modified oligonucleotides in HepaRG cells %inhibition HSD17B13 ION IC₅₀ No. 20 nM 78 nM 313 nM 1250 nM 5000 nM (μM)1246023 0 7 18 81 92 0.6 1341531 18 21 38 62 76 0.6 1341561 26 22 39 7570 0.4 1341644 0 11 60 82 90 0.4 1341645 0 20 0 39 79 1.8 1341646 3 0 857 76 1.3 1341968 0 0 10 72 90 0.8 1341980 8 9 26 54 78 1.0

Example 6: Design of Human HSD17B13 Modified Oligonucleotides

Certain modified oligonucleotides described above were further modifiedby conjugating at the 5′-end with a LICA-1 moiety. The resultingcompounds and their unconjugated counterparts are listed in the tablebelow. The compounds have identical sequence and oligonucleotidechemistry as the “parent compounds” described above.

TABLE 77 Design of 5′-LICA-1-conjugated modifiedoligonucleotides targeting human HSD17B13 GalNac Conjugated Parent SEQCompound Compound Sequence ID No. No. (5′ to 3′) NO 1310535 1246163CAACTATGTAATAGGC 286 1371966 1245806 AAAATAGAGTCGGTCA 817 13719681246068 AGCATAAGTTACCAGA 983 1371969 1246115 AAATTATACTTTTCCG 5961371971 1246063 GTTTTATAACTGAGCT 594 1371973 1246019 GAATTTTTGAGGTTGG1215 1371974 1245987 TCTCAAGGAGTACTTC 747 1371976 1245952GTCATAAAAATCGCTG 43 1371978 1245930 AAGATAAGTAGATGGT 355 1371979 1245972GCACTAAAGGTTTCTG 1602 1371981 1245980 ATACTAATGTCCAAGG 201 13730861245649 CTACTTGAACAGTCTT 734 1373087 1246903 AGTTAGTATAGTTATC 12491373089 1246134 CTCATTTATGTACCAA 51 1373090 1246162 ACTATGTAATAGGCAG 2081373097 1245984 ACAATTTTTCCAATCC 513 1373098 1246022 AGTGAATCATTCAGTA1449 1373099 1245996 CATTCGAATTTCTTCA 1448 1373101 1245790GTATCTTATAAGACTA 1595 1394140 1341675 CTACUTGAACAGTCTT 2868 13941411340820 GTAGATGGTAAGTCAA 2567 1394142 1341283 TGATATTCTGTGGCAT 11241394143 1341313 TATGTAATAGCCAGTA 508 1394144 1341742 GTATCTTATAAGACTA1595 1394145 1341038 TTCTTATGTAATAGCC 819 1394146 1341735CACCGTTTTGGGCTAA 1516 1394147 1341032 TTATGTAATAGCCAGT 586 13941481341108 GCATCTTAAGATACCC 553 1394149 1340435 TAGAACTGTGTTGCTT 25351394150 1340908 TAGAGTGAATCATTCA 2420 1394151 1340208 GAGTAGTGTAAGCTGA2204 1394152 1340782 GAGATTTGAAGGTTAG 2561 1371970 1246157GCAGTAAAGTGCTAAG 1843 1371972 1246025 AGCCTTAGAGTGAATC 1682 13730941246036 TGAAAACTCAGCCAGC 515 1373096 1245968 GTAATTTTCAGATCCC 12911373100 1245682 GTTGATATTCTGTGGC 1280

Example 7: Dose-Dependent Ex-Vivo Inhibition of Human HSD17B13 inTransgenic Mouse Hepatocytes

The conjugated modified oligonucleotides described above were tested forinhibition of HSD17B13 RNA at various doses in primary mouse hepatocytesextracted from transgenic mice.

A transgenic mouse model was developed in-house using a Fosmidcontaining the human HSD17B13 gene (NCBI Clone DB ID: ABC8-43206400A10).The clone was digested at Not1 restriction sites (2 different sites) toproduce a fragment containing 19,118 bp of the human HSD17B13 gene,including 12,175 bp upstream and 7,553 bp downstream regions. That genefragment was introduced into fertilized eggs from C57/BL/6NTac strainmice by pronuclear injection to produce huHSD 17469 and 17470 founderlines. Transgenic mice derived from Founder Line 17469 was used in theexperiments described herein. Human HSD17B13 RNA expression is found inthe liver in this model. Mice were sacrified and hepatocytes werecollected for use in experiments testing conjugated modifiedoligonucleotides.

The conjugated modified oligonucleotides were tested in a series ofexperiments using the same culture conditions. The results for eachexperiment are presented in separate tables shown below. Primary mousetransgenic hepatocytes described above were plated at a density of20,000 cells per well and were treated by free uptake with conjugatedmodified oligonucleotides diluted to different concentrations asspecified in the tables below. After an overnight incubation, HSD17B13RNA levels were measured as previously described herein using the HumanHSD17B13 primer-probe set RTS43553. HSD17B13 RNA levels were normalizedto total GAPDH content. Results are presented in the tables below aspercent inhibition of HSD17B13, relative to untreated control cells. Thehalf maximal inhibitory concentration (IC₅₀) of each modifiedoligonucleotide was calculated using a linear regression on a log/linearplot of the data in excel and is also presented in the Tables below.

TABLE 78 Multi-dose assay of modified oligonucleotides in primary mousehepatocytes % Inhibition ION 1.95 7.81 31.25 125 500 2000 IC₅₀ No. nM nMnM nM nM nM (nM) 1310535 38 53 80 87 85 90 3.2 1371966 41 52 87 88 91 894.1 1371968 39 56 84 94 91 90 4.1 1371969 23 60 81 88 88 92 5.2 13719716 45 54 70 85 76 34.1 1371973 38 61 84 93 94 96 2.2 1371974 4 31 65 7474 82 38.6 1371976 16 62 79 87 90 93 7.3 1371978 0 39 84 92 89 88 18.41371979 10 38 70 82 85 87 21.0 1371981 33 68 86 94 93 95 1.9

TABLE 79 Multi-dose assay of modified oligonucleotides in primary mousehepatocytes % Inhibition ION 1.95 7.81 31.25 125 500 2000 IC₅₀ No. nM nMnM nM nM nM (nM) 1373086 24 49 78 83 86 84 8.9 1373087 23 20 67 70 64 6522.6 1373089 36 62 84 92 91 92 4.0 1373090 43 49 69 81 80 82 5.4 137309741 64 84 89 92 91 1.3 1373098 43 69 80 87 89 89 2.3 1373099 19 37 68 8483 86 13.8 1373101 9 41 66 83 85 92 20.5 1394140 5 42 80 78 85 88 19.61394142 5 49 73 87 89 91 16.4 1371966 4 55 77 88 88 87 11.5

TABLE 80 Multi-dose assay of modified oligonucleotides in primary mousehepatocytes % Inhibition ION 1.95 7.81 31.25 125 500 2000 IC₅₀ No. nM nMnM nM nM nM (nM) 1394143 19 45 80 83 89 89 10.6 1394144 16 21 54 70 7580 48.1 1394145 37 44 83 91 88 88 6.2 1394146 3 30 67 74 82 77 38.21394147 30 71 85 94 94 93 4.0 1394148 41 80 88 90 87 91 1.7 1394149 1 2656 72 78 82 50.9 1394150 14 45 80 84 88 85 12.8 1394151 0 37 63 81 83 8542.5 1394152 8 35 63 82 81 87 28.1 1371966 0 61 72 82 89 88 16.7

Example 8: Tolerability of Modified Oligonucleotides Complementary toHuman HSD17B13 in CD-1 Mice

CD-1 mice are a multipurpose mouse model frequently utilized for safetyand efficacy testing. In this study, CD-1 mice were treated withconjugated modified oligonucleotides selected from studies describedabove and evaluated for changes in the levels of various plasmachemistry markers.

Treatment

Groups of 6- to 8-week-old male CD-1 mice were injected subcutaneouslyonce a week for six weeks (for a total of 7 treatments) with 25 mg/kg ofconjugated modified oligonucleotides. One group of male CD-1 mice wasinjected with PBS. Mice were euthanized 48 hours following the finaladministration.

Study 1 Plasma Chemistry Markers

To evaluate the effect of conjugated modified oligonucleotides on liverfunction, plasma levels of blood urea nitrogen (BUN), albumin, alanineaminotransferase (ALT), aspartate aminotransferase (AST), and creatinine(CREA) were measured using an automated clinical chemistry analyzer(Hitachi Olympus AU400c, Melville, N.Y.). The results are presented inthe table below.

TABLE 81 Plasma chemistry markers in male CD-1 mice ION Albumin ALT ASTCREA BUN NO. (g/dL) (IU/L) (IU/L) (mg/dL) (mg/dL) PBS 2.5 25 52 0.2 231310535 2.6 32 44 0.2 24 1371966 2.7 31 40 0.2 23 1371968 2.7 26 42 0.223 1371969 2.6 28 59 0.2 24 1371970 2.6 277 225 0.2 24 1371971 2.8 41 740.2 24 1371972 2.4 810 568 0.2 24 1371973 2.3 50 78 0.2 22 1371974 2.760 61 0.2 25 1371976 2.7 32 61 0.2 22 1371978 2.7 51 59 0.2 21 13719792.7 32 70 0.2 23

Body and Organ Weights

Body weights of CD-1 mice were measured at days 1 and 44, and theaverage body weight for each group is presented in the table below.Liver, kidney and spleen weights were measured at the end of the studyand are presented in the table below.

TABLE 82 Body and organ weights (in grams) ION Body Weight (g) LiverKidney Spleen No. Day 1 Day 44 (g) (g) (g) PBS 34 42 2.4 0.5 0.1 131053533 42 2.4 0.6 0.1 1371966 32 39 2.2 0.6 0.1 1371968 30 38 2.1 0.5 0.11371969 33 43 2.4 0.5 0.1 1371970 29 36 2.1 0.5 0.1 1371971 33 41 2.50.6 0.2 1371972 33 40 3.1 0.7 0.2 1371973 31 38 1.7 0.5 0.1 1371974 3440 2.4 0.6 0.1 1371976 32 40 2.4 0.6 0.1 1371978 32 38 2.4 0.5 0.11371979 33 38 2.3 0.6 0.1

Hematology Assays

Blood obtained from mouse groups at week 6 and was sent to IDEXXBioResearch for measurement of hematocrit (HCT), and platelet counts(PLT). The results are presented in the table below.

TABLE 83 Blood cell counts in male CD-1 mice ION NO. HCT (%) PLT (10⁹/L)PBS 46 1155 1310535 50 1389 1371966 46 1415 1371968 47 1372 1371969 451059 1371970 48 1395 1371971 46 1244 1371972 44 1360 1371973 47 9681371974 45 1362 1371976 49 1199 1371978 47 1417 1371979 48 1190

Study 2 Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of blood urea nitrogen (BUN), albumin, alanineaminotransferase (ALT), aspartate aminotransferase (AST), and creatinine(CREA) were measured using an automated clinical chemistry analyzer(Hitachi Olympus AU400c, Melville, N.Y.). The results are presented inthe table below.

TABLE 84 Plasma chemistry markers in male CD-1 mice ION Albumin ALT ASTCREA BUN NO. (g/dL) (IU/L) (IU/L) (mg/dL) (mg/dL) PBS 2.8 36 57 0.11 191371981 2.7 26 39 0.14 24 1373086 2.6 39 59 0.12 24 1373087 2.6 31 540.13 23 1373089 2.5 107 88 0.12 24 1373090 2.5 27 45 0.11 25 1373094 2.8687 532 0.15 23 1373096 2.7 57 87 0.13 23 1373097 2.4 67 71 0.13 231373098 2.5 67 73 0.12 24 1373099 2.7 43 75 0.12 22 1373100 2.7 373 3650.12 25 1373101 2.5 153 179 0.14 23

Body and Organ Weights

Body weights of CD-1 mice were measured at days 1 and 42, and theaverage body weight for each group is presented in the table below.Liver, kidney and spleen weights were measured at the end of the studyand are presented in the table below.

TABLE 85 Body and organ weights (in grams) ION Body Weight (g) LiverKidney Spleen No. Day 1 Day 42 (g) (g) (g) PBS 27 38 1.9 0.6 0.1 137198127 39 2.5 0.6 0.1 1373086 27 38 2.1 0.5 0.1 1373087 27 40 2.4 0.6 0.11373089 26 39 2.8 0.5 0.1 1373090 27 38 2.4 0.5 0.2 1373094 28 41 2.90.6 0.2 1373096 27 42 2.5 0.6 0.2 1373097 27 42 2.52 0.49 0.17 137309827 39 2.48 0.51 0.13 1373099 27 39 2.44 0.61 0.14 1373100 26 37 2.110.52 0.16 1373101 29 45 2.68 0.63 0.20

Hematology Assays

Blood obtained from mouse groups at week 6 and was sent to IDEXXBioResearch for measurement of hematocrit (HCT), platelet counts (PLT),neutrophil counts (NEU), reticulocyte counts (RET) and lymphocyte counts(LYM). The results are presented in the table below.

TABLE 86 Blood cell counts in male CD-1 mice ION HCT PLT NEU RET LYM NO.(%) (10³/μL) (%) (%) (%) PBS 45 1150 19 3 77 1371981 46 1398 18 3 761373086 44 1415 17 3 74 1373087 42 1343 21 3 73 1373089 43 1216 21 3 721373090 42 1332 21 3 52 1373094 44 1307 24 3 68 1373096 47 1161 19 3 691373097 42 1394 25 3 67 1373098 44 1432 24 4 68 1373099 44 1201 20 3 751373100 41 1031 16 3 77 1373101 45 1236 28 4 65

Study 3 Plasma Chemistry Markers

To evaluate the effect of modified oligonucleotides on liver function,plasma levels of blood urea nitrogen (BUN), albumin, alanineaminotransferase (ALT), aspartate aminotransferase (AST), totalbilirubin (TBIL) and creatinine (CREA) were measured using an automatedclinical chemistry analyzer (Hitachi Olympus AU400c, Melville, N.Y.).The results are presented in the table below.

TABLE 87 Plasma chemistry markers in male CD-I mice ION Albumin ALT ASTCREA BUN TBIL NO. (g/dL) (IU/L) (IU/L) (mg/dL) (mg/dL) (mg/dL) PBS 2.825 56 0.1 26 0.2 1394140 2.9 38 72 0.2 24 0.2 1394142 2.5 67 92 0.1 230.2 1394143 2.7 30 55 0.1 22 0.2 1394144 2.7 37 69 0.1 24 0.2 13941452.7 50 67 0.1 25 0.1 1394146 2.8 142 203 0.1 24 0.2 1394147 2.5 63 800.1 25 0.1 1394148 3.1 219 193 0.1 23 0.2 1394149 2.9 746 757 0.2 25 0.31394150 2.7 608 451 0.1 22 0.2

Body and Organ Weights

Body weights of CD-1 mice were measured at days 1 and 39, and theaverage body weight for each group is presented in the table below.Liver, kidney and spleen weights were measured at the end of the studyand are presented in the table below.

TABLE 88 Body and organ weights (in grams) ION Body Weight (g) LiverKidney Spleen No. Day 1 Day 39 (g) (g) (g) PBS 29 36 1.8 0.5 0.1 139414028 36 2.0 0.5 0.1 1394142 30 38 1.8 0.5 0.2 1394143 29 37 2.1 0.5 0.11394144 29 37 2.1 0.5 0.1 1394145 30 38 2.4 0.5 0.2 1394146 29 37 2.10.5 0.1 1394147 31 38 2.5 0.5 0.2 1394148 29 37 2.6 0.5 0.2 1394149 2735 2.3 0.4 0.1 1394150 27 35 2.3 0.5 0.2

Hematology Assays

Blood obtained from mouse groups at week 6 were sent to IDEXXBioResearch for measurement of hematocrit (HCT), platelet counts (PLT),neutrophil counts (NEU), reticulocyte counts (RET) and lymphocyte counts(LYM). The results are presented in the table below.

TABLE 89 Blood cell counts in male CD-1 mice ION HCT PLT NEU RET LYM NO.(%) (10³/μL) (%) (%) (%) PBS 53 1271 17 3 74 1394140 52 1221 20 3 721394142 50 1249 28 3 64 1394143 50 1165 17 3 76 1394144 49 1090 18 3 751394145 52 1292 21 3 73 1394146 50 1382 27 3 66 1394147 52 1343 22 3 691394148 52 1286 27 3 64 1394149 46 1613 26 3 66 1394150 47 1444 13 2 79

Example 9: Tolerability of Modified Oligonucleotides Targeting HumanHSD17B13 in Sprague-Dawley Rats

Sprague-Dawley rats are a multipurpose model used for safety andefficacy evaluations. In this study, the rats were treated with Ionisconjugated modified oligonucleotides from the studies described in theExamples above and evaluated for changes in the levels of various plasmachemistry markers.

Treatment

Male Sprague-Dawley rats were maintained on a 12-hour light/dark cycleand fed ad libitum with Purina normal rat chow. Groups of 4Sprague-Dawley rats each were weekly injected subcutaneously with 25mg/kg of conjugated modified oligonucleotide for 6 weeks (total 7doses). 72 hours after the last dose, rats were euthanized; and organs,urine and plasma were harvested for further analysis.

Study 1 Plasma Chemistry Markers

To evaluate the effect of the conjugated modified oligonucleotides onhepatic function, plasma levels of transaminases were measured using anautomated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville,N.Y.). Plasma levels of ALT (alanine transaminase) and AST (aspartatetransaminase) were measured and the results are presented in the Tablebelow expressed in IU/L. Plasma levels of creatinine (CREA), albumin,and Blood Urea Nitrogen (BUN) were also measured using the same clinicalchemistry analyzer and the results are also presented in the tablebelow.

TABLE 90 Plasma chemistry markers in Sprague-Dawley rats ION Albumin ALTAST CREA BUN NO. (g/dL) (IU/L) (IU/L) (mg/dL) (mg/dL) PBS 3.4 34 53 0.313 1310535 3.2 35 68 0.3 14 1371966 3.5 33 66 0.3 16 1371968 3.8 36 570.4 16 1371969 3.0 25 68 0.3 16 1371970 3.4 48 101 0.3 15 1371971 3.6 3472 0.3 16 1371972 3.5 51 76 0.4 15 1371973 3.6 36 62 0.3 14 1371974 3.337 76 0.4 15 1371976 3.4 31 55 0.3 15 1371978 3.4 37 67 0.3 15 13719793.5 117 122 0.3 12

Hematology Assays

Blood obtained from mouse groups at week 6 and was sent to IDEXXBioResearch for measurement of hematocrit (HCT), and platelet counts(PLT). The results are presented in the table below.

TABLE 91 Blood Cell Count in Sprague-Dawley Rats ION NO. HCT (%) PLT(10⁹/L) PBS 47 849 1310535 43 954 1371966 46 844 1371968 47 1010 137196943 810 1371970 48 1016 1371971 46 893 1371972 46 1019 1371973 44 8571371974 46 930 1371976 45 843 1371978 45 900 1371979 47 1077

Kidney Function

To evaluate the effect of the conjugated modified oligonucleotides onkidney function, urinary levels of total protein and creatinine weremeasured using an automated clinical chemistry analyzer (Hitachi OlympusAU400c, Melville, N.Y.). The ratios of total protein to creatinine (P/Cratio) are presented in the table below.

TABLE 92 Total protein to creatinine ratio in Sprague-Dawley rats IONNO. Urine P/C Ratio PBS 0.5 1310535 0.4 1371966 0.8 1371968 0.7 13719690.6 1371970 0.6 1371971 1.1 1371972 0.4 1371973 0.7 1371974 0.8 13719760.7 1371978 0.5 1371979 0.8

Body and Organ Weights

Body weights of Sprague-Dawley rats were measured at days 1 and 40, andthe average body weight for each group is presented in the table below.Liver, heart, spleen and kidney weights were measured at the end of thestudy and are presented in the table below.

TABLE 93 Body and Organ weights In Sprague-Dawley rats (g) ION BodyWeight (g) Kidney Spleen No. Day 1 Day 40 Liver (g) (g) (g) PBS 140 46418 3.2 1.1 1310535 152 476 20 3.7 1.5 1371966 150 437 17 3.1 1.0 1371968147 419 15 2.9 1.0 1371969 151 423 16 3.5 2.0 1371970 151 440 16 2.9 1.11371971 138 406 17 3.1 1.4 1371972 144 424 12 2.7 1.0 1371973 141 401 143.0 1.3 1371974 143 443 16 3.0 1.1 1371976 126 412 16 2.8 1.0 1371978155 452 17 3.3 1.3 1371979 148 458 19 3.1 1.3

Study 2 Plasma Chemistry Markers

To evaluate the effect of the conjugated modified oligonucleotides onhepatic function, plasma levels of transaminases were measured using anautomated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville,N.Y.). Plasma levels of ALT (alanine transaminase) and AST (aspartatetransaminase) were measured and the results are presented in the Tablebelow expressed in IU/L. Plasma levels of creatinine (CREA), albumin,and Blood Urea Nitrogen (BUN) were also measured using the same clinicalchemistry analyzer and the results are also presented in the tablebelow.

TABLE 94 Plasma chemistry markers in Sprague-Dawley rats ION Albumin ALTAST CREA BUN NO. (g/dL) (IU/L) (IU/L) (mg/dL) (mg/dL) PBS 3.6 33 56 0.316 1371981 3.7 35 57 0.3 17 1373086 3.7 35 87 0.4 19 1373087 3.3 33 640.4 18 1373089 3.7 92 129 0.3 18 1373090 3.5 38 72 0.4 18 1373094 3.7187 311 0.4 16 1373096 3.3 69 171 0.3 18 1373097 3.2 40 86 0.3 171373098 3.8 37 74 0.3 17 1373099 3.6 33 60 0.4 16 1373100 3.1 39 115 0.320 1373101 3.4 37 80 0.3 14

Hematology Assays

Blood obtained from mouse groups at week 6 were sent to IDEXXBioResearch for measurement of hematocrit (HCT), and platelet counts(PLT), neutrophil counts (NEU), reticulocyte counts (RET) and lymphocytecounts (LYM). The results are presented in the table below.

TABLE 95 Blood Cell Count in Sprague-Dawley Rats ION HCT PLT NEU RET LYMNO. (%) (10³/μL) (%) (%) (%) PBS 51 709 14 3 72 1371981 52 769 11 2 841373086 47 921 8 2 88 1373087 50 764 6 3 89 1373089 49 1217 7 3 881373090 50 766 10 4 85 1373094 53 943 14 2 81 1373096 61 376 6 3 891373097 49 746 5 3 90 1373098 49 929 10 3 85 1373099 47 717 8 3 851373100 42 823 6 4 87 1373101 48 693 7 3 87

Kidney Function

To evaluate the effect of Ionis oligonucleotides on kidney function,urinary levels of total protein and creatinine were measured using anautomated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville,N.Y.). The ratios of total protein to creatinine (P/C ratio) arepresented in the table below.

TABLE 96 Total protein to creatinine ratio in Sprague-Dawley rats IONNO. Urine P/C Ratio PBS 1.0 1371981 1.7 1373086 1.5 1373087 1.7 13730891.5 1373090 1.3 1373094 3.3 1373096 1.5 1373097 1.3 1373098 1.2 13730991.9 1373100 0.9 1373101 1.7

Body and Organ Weights

Body weights of Sprague-Dawley rats were measured at days 1 and 44, andthe average body weight for each group is presented in the table below.Liver, heart, spleen and kidney weights were measured at the end of thestudy and are presented in the table below.

TABLE 97 Body and Organ weights In Sprague-Dawley rats (g) ION BodyWeight (g) Liver Kidney Spleen No. Day 1 Day 44 (g) (g) (g) PBS 146 45819 3.1 1.0 1371981 141 424 21 3.4 1.1 1373086 151 434 19 3.0 1.8 1373087143 433 19 3.3 1.3 1373089 149 431 21 3.5 2.1 1373090 142 453 19 3.2 1.31373094 142 449 19 3.2 1.4 1373096 149 460 23 3.6 3.2 1373097 136 400 173.3 2.2 1373098 130 389 20 2.9 1.5 1373099 152 421 16 2.9 1.6 1373100146 453 19 4.2 2.3 1373101 140 412 17 2.9 1.5

Study 3 Plasma Chemistry Markers

To evaluate the effect of the conjugated modified oligonucleotides onhepatic function, plasma levels of transaminases were measured using anautomated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville,N.Y.). Plasma levels of ALT (alanine transaminase) and AST (aspartatetransaminase) were measured and the results are presented in the Tablebelow expressed in IU/L. Plasma levels of creatinine (CREA), albumin,total bilirubin (TBIL) and Blood Urea Nitrogen (BUN) were also measuredusing the same clinical chemistry analyzer and the results are alsopresented in the table below.

TABLE 98 Plasma chemistry markers in Sprague-Dawley rats ION Albumin ALTAST CREA BUN TBIL NO. (g/dL) (IU/L) (IU/L) (mg/dL) (mg/dL) (mg/dL) PBS3.2 41 62 0.3 18 0.2 1394140 3.6 48 123 0.4 20 0.3 1394142 3.0 57 1360.4 23 0.2 1394143 3.3 122 201 0.3 19 0.4 1394144 3.2 38 73 0.4 18 0.11394145 3.6 112 187 0.4 17 0.2 1394146 3.4 54 98 0.4 20 0.2 1394147 3.153 110 0.3 18 0.2 1394148 3.5 45 57 0.4 19 0.3 1394149 3.7 94 102 0.5 270.3 1394150 3.8 60 83 0.4 19 0.2

Hematology Assays

Blood obtained from mouse groups at week 6 and was sent to IDEXXBioResearch for measurement of hematocrit (HCT), and platelet counts(PLT), neutrophil counts (NEU), reticulocyte counts (RET) and lymphocytecounts (LYM). The results are presented in the table below.

TABLE 99 Blood Cell Count in Sprague-Dawley Rats ION HCT PLT NEU RET LYMNO. (%) (K/μL) (%) (%) (%) PBS 52 795 12 3 84 1394140 45 876 8 3 881394142 47 768 4 3 90 1394143 59 1277 11 2 80 1394144 51 574 6 3 871394145 51 806 12 2 82 1394146 48 1052 11 2 81 1394147 49 922 8 3 851394148 49 1134 12 3 84 1394149 46 1816 14 3 80 1394150 52 1094 12 3 83

Kidney Function

To evaluate the effect of Ionis oligonucleotides on kidney function,urinary levels of total protein and creatinine were measured using anautomated clinical chemistry analyzer (Hitachi Olympus AU400c, Melville,N.Y.). The ratios of total protein to creatinine (P/C ratio) arepresented in the table below.

TABLE 100 Total protein to creatinine ratio in Sprague-Dawley rats IONNO. Urine P/C Ratio PBS 0.8 1394140 1.6 1394142 1.1 1394143 1.3 13941441.3 1394145 1.1 1394146 1.8 1394147 1.5 1394148 1.0 1394149 1.1 13941501.9

Body and Organ Weights

Body weights of Sprague-Dawley rats were measured at days 1 and 42, andthe average body weight for each group is presented in the table below.Liver, heart, spleen and kidney weights were measured at the end of thestudy and are presented in the table below.

TABLE 101 Body and Organ weights In Sprague-Dawley rats (g) ION BodyWeight (g) Liver Kidney Spleen No. Day 1 Day 42 (g) (g) (g) PBS 270 50319 3.0 0.9 1394140 263 440 19 3.0 1.5 1394142 258 370 13 2.9 1.5 1394143257 393 16 2.9 1.1 1394144 254 461 18 3.2 1.5 1394145 266 475 21 3.4 1.41394146 268 444 17 3.1 1.7 1394147 258 401 17 3.2 2.0 1394148 267 447 213.0 1.5 1394149 261 422 20 5.8 1.4 1394150 251 423 18 3.0 1.2

Example 10: Measurement of Viscosity of Modified OligonucleotidesTargeting Human HSD17B13

The viscosity of select conjugated modified oligonucleotides from thestudies described above was measured.

Conjugated modified oligonucleotides (within a range of 32-38 mg) wereplaced into separate glass vials; approximately 100 μL of water wasadded to each vial, and the conjugated modified oligonucleotides weredissolved into solution by heating the vials to 55° C. A 75 μL portionof the pre-heated sample was pipetted to a micro-viscometer (PACCambridge Viscosity Viscometer). The temperature of the micro-viscometerwas set to 25° C. and the viscosity of the sample was measured. The 75uL portion of each sample was then combined with the remaining portionof the original sample, which was then diluted for UV reading at 260 nM(Cary UV instrument). The data is presented in the Table below.Compounds having viscosity of less that 40 cP in this assay aregenerally suitable for use in therapy.

TABLE 102 Viscosity of modified oligonucleotides ConcentrationConcentration Compound by weight by UV Viscocity ID (mg/mL) (mg/mL) (cP)1310535 300 206 6 1371966 300 223 10 1371974 300 207 8 1371976 300 25464 1371978 300 219 7 1371979 300 244 10 1373086 300 215 7 1373087 300219 9 1373090 300 191 8 1373097 300 222 6 1373098 300 203 5 1373099 300242 6 1373101 300 205 11 1394140 300 197 10 1394141 300 225 9 1394142300 271 24 1394143 300 250 11 1394144 300 257 32 1394145 300 263 101394146 300 289 11 1394147 300 246 15 1394148 300 205 9 1394149 300 30414 1394150 300 202 16 1394151 300 223 8 1394152 300 225 24 1371976 200151 16

1-108. (canceled)
 109. An oligomeric compound, according to thefollowing chemical structure:

or a pharmaceutically acceptable salt thereof.
 110. An oligomericcompound, according to the following chemical structure:


111. An oligomeric compound comprising a modified oligonucleotideconsisting of 16 linked nucleosides having a nucleobase sequence SEQ IDNO: 1448, wherein the modified oligonucleotide comprises a gap segmentconsisting of ten linked deoxynucleosides; a 5′ wing segment consistingof three linked nucleosides; and a 3′ wing segment consisting of threelinked nucleosides; wherein the gap segment is positioned between the 5′wing segment and the 3′ wing segment; wherein the 5′ wing segment andthe 3′ wing segment comprise cEt sugars; wherein each internucleosidelinkage is a phosphorothioate linkage; and wherein each cytosine is a5-methylcytosine.
 112. The oligomeric compound of claim 109, which is asodium salt or a potassium salt.
 113. A pharmaceutical compositioncomprising the oligomeric compound of any one of claims 109-112 and apharmaceutically acceptable diluent.
 114. The pharmaceutical compositionof claim 113, wherein the pharmaceutically acceptable diluent is water.115. A method of treating a disease associated with HSD17B13 in anindividual comprising administering to the individual a compound of anyone of claims 109-112, thereby treating the disease.
 116. The method ofclaim 115, wherein the individual has a liver disease, NAFLD, NASH,alcoholic steatohepatitis (ASH), alcoholic liver disease, nonalcoholicliver disease, alcoholic cirrhosis, nonalcoholic cirrhosis,steatohepatisis, hepatic steatosis, hepatocellular carcinoma, alcoholicliver disease, HCV hepatitis, chronic hepatitis, hereditaryhemochromatosis, or primary sclerosing cholangitis.
 117. A method ofinhibiting expression of HSD17B13 in a cell comprising contacting thecell with an oligomeric compound of any one of claims 109-112, therebyinhibiting expression of HSD17B13 in the cell.
 118. The method of claim117, wherein the cell is in the liver of an individual.
 119. The methodof claim 118, wherein the individual has, or is at risk of having, liverdisease, NAFLD, NASH, alcoholic steatohepatitis (ASH), alcoholic liverdisease, nonalcoholic liver disease, alcoholic cirrhosis, nonalcoholiccirrhosis, steatohepatisis, hepatic steatosis, hepatocellular carcinoma,alcoholic liver disease, HCV hepatitis, chronic hepatitis, hereditaryhemochromatosis, or primary sclerosing cholangitis.
 120. A method ofameliorating liver damage, steatosis, liver fibrosis, liverinflammation, liver scarring or cirrhosis, liver failure, liverenlargement, elevated transaminases, or hepatic fat accumulation in anindividual, comprising administering an oligomeric compound of any oneof claims 109-112 to the individual, thereby ameliorating liver damage,steatosis, liver fibrosis, liver inflammation, liver scarring orcirrhosis, liver failure, liver enlargement, elevated transaminases, orhepatic fat accumulation in the individual.
 121. The method of claim120, wherein the individual has, or is at risk of having, liver disease,NAFLD, NASH, alcoholic steatohepatitis (ASH), alcoholic liver disease,nonalcoholic liver disease, alcoholic cirrhosis, nonalcoholic cirrhosis,steatohepatisis, hepatic steatosis, hepatocellular carcinoma, alcoholicliver disease, HCV hepatitis, chronic hepatitis, hereditaryhemochromatosis, or primary sclerosing cholangitis.